4-azaindole derivatives

ABSTRACT

4-Azaindole derivatives which are modulators of muscarinic acetylcholine receptor (mAChR) M1 and which may be effective for the prevention or disease modifying or symptomatic treatment of cognitive deficits associated with neurological disorders such as Alzheimer-type dementia (AD) or dementia with Lewy bodies (DLB), and a pharmaceutical composition comprising a 4-azaindole derivative as an active ingredient.

FIELD OF THE INVENTION

The present invention relates to 4-azaindole derivatives and thepharmaceutical use thereof. More particularly, the present inventionrelates to 4-azaindole derivatives which are modulators of muscarinicacetylcholine receptor (mAChR) M1 (mAChR M1) and may be effective forthe prevention or disease modifying or symptomatic treatment ofcognitive deficits associated with neurological disorders such asAlzheimer-type dementia (AD) or dementia with Lewy bodies (DLB), and toa pharmaceutical composition comprising a 4-azaindole derivative as anactive ingredient.

BACKGROUND

It is believed that cholinergic hypofunction contributes to thecognitive deficits associated with Alzheimer's disease (Science, 1982,215, 1237-1239) and acetylcholinesterase inhibitors, which inhibitacetylcholine hydrolysis, are used clinically for the treatment ofcognitive impairment in Alzheimer's disease. Cholinergic deficits arealso prominent in dementia with Lewy bodies (DLB) and when administeredto patients with DLB the cholinesterase inhibitor donepezil has beenreported to give significant improvements in behavioural measures (Ann.Neurol., 2012, 72(1), 41-52). Therefore, activation of centralcholinergic neurotransmission via enhanced signalling of muscarinicreceptors may be effective for the symptomatic treatment of cognitivedeficits associated with neurological disorders such as AD or DLB.

Muscarinic acetylcholine receptors are G-protein coupled receptors thatmediate the actions of the neurotransmitter acetylcholine. Five distinctmammalian mAChR subtypes (M1-M5) have been identified in mammals. mAChRM1 which is predominantly expressed in the cortex, hippocampus andstriatum, has been found to have an important role in cognitiveprocessing (Psychopharmacology, 1987, 93, 470-476; Behav. Brain Res.1988, 27, 9-20; Nature Neuroscience, 2002, 6, 51-58) and, more recently,has also been implicated as having a potential role in modifyingAlzheimer's disease progression (Proc. Natl. Acad. Sci. USA, 1992, 89,10075-10078). However, other muscarinic subtypes, in addition to beingexpressed centrally are also expressed peripherally e.g. mAChR M2 isexpressed in cardiac tissue and in smooth muscle whilst mAChR M3 isexpressed in sweat and salivary glands (Pharmacology and Therapeutics,2008, 117, 232). As a result, muscarinic activation by non-selectiveagonists has resulted in dose-limiting peripheral cholinergicside-effects which may be attributed to their relative lack ofselectivity. Selective mAChR M1 activation may therefore prove useful inthe treatment of cognitive impairment, including diseases such asAlzheimer's disease and DLB, as well as for the treatment of cognitivedisorders associated with psychotic disorders such as schizophrenia, butwithout the peripheral cholinergic side-effects mediated predominantlythrough mAChR M2 and mAChR M3.

Since the orthosteric acetylcholine binding site is highly conservedacross the muscarinic family, obtaining selective mAChR M1 orthostericligands may prove challenging. However, recent advances in theunderstanding of alternative binding motifs and receptor states (Trendsin Pharmacological Sciences, 2009, 30, 460-469) has identified thepossibility of allosteric binding sites which are distinct from theendogenous ligand site and thus potentially much less conserved acrossthe family. mAChR M1 is known to contain one or more such allostericsites, which may alter the affinity with which muscarinic ligands bindto the primary binding or orthosteric sites or affect downstreamsignalling (Molecular Pharmacology, 2000, 58, 194-207; MolecularPharmacology, 2002, 62, 1492-1505). Positive Allosteric Modulators (PAM)of mAChR M1 are thus expected to be useful in enhancing muscarinicreceptor function in a selective fashion, avoiding many of the potentialside effects associated with activation of other muscarinic subtypes(Trends in Pharmacological Sciences, 2009, 30, 148-155).

mAChR M1PAM compounds have been investigated as potential therapies forcognitive impairment associated with neurological disorders such asdementia (for example dementia associated with Alzheimer's disease),mild cognitive impairment and age related cognitive decline and also forpsychiatric disorders such as schizophrenia, for example as described inWO2009094279, WO2011075371, WO2012158473, WO2013063549 and WO2013091773.

Examples of other diseases that might be treatable or preventable with acompound which acts as a modulator of mAChR M1 are: Huntington'sdisease, amyotrophic lateral sclerosis (ALS), post-operative cognitivedeficit (POCD), Parkinson's disease, Parkinson's dementia, Down'ssyndrome, cognitive deficits in various forms of mild cognitiveimpairment, cognitive deficits in various forms of dementia, dementiapugilistica, vascular and frontal lobe dementia, cognitive impairment,learning impairment, attention deficit hyperactivity disorder (ADHD),attention deficit syndrome (ADS), cognitive disorders related to drugabuse including cocaine abuse, cognitive disorders related to nicotinewithdrawal, autism, dementia, dementia in Korsakoff syndrome, Korsakoffsyndrome, vascular dementia, dementia related to HIV infections, HIV-1encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-relateddementia, major depressive disorder, major depression, depression,depression resulting from Borna virus infection, major depressionresulting from Borna virus infection, bipolar manic-depressive disorder,fragile-X syndrome, autism-spectrum disorders, pain, chronic pain, acutepain, inflammatory pain, neuropathic pain, diabetic neuropathic pain(DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia,nociceptive pain, cancer pain, positive or negative or cognitivesymptoms of schizophrenia, sleep disorders, delusional disorder,schizoaffective disorder, schizophreniform disorder, substance-inducedpsychotic disorder, or delirium, sleep disturbances, synucleinopathies,alpha-synucleinopathies, neurodegeneration with Brain Iron Accumulation,Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy(PSP), frontotemporal dementia and parkinsonism linked to chromosome 17(FTDP-17), and other neurodegenerative diseases.

SUMMARY OF THE INVENTION

An object of the present invention is to provide compounds that aremodulators of mAChR M1 which may be useful as prophylactic ortherapeutic agents for a neurological disorder such as Alzheimer-typedementia (AD) or dementia with Lewy bodies (DLB). In particular, anobject of the present invention is to provide compounds that arepositive allosteric modulators of mAChR M1.

The present invention relates to a series of 4-azaindole derivativeswhich may act as positive allosteric modulators of mAChR M1. Specificaspects according to the present invention are:—

[1] A compound or a pharmaceutically acceptable salt thereof, which is

-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-((5-fluoropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,4-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(trans-2-hydroxycycloheptyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-cyano-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-5-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-(6-methylpyridin-2-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-(2-methylpyridin-4-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(trans-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (S)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (S)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (R)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-bromobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxy-3-methylbenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-((6-cyanopyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((5-chloropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluoro-4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(3-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-fluorobenzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;    or-   7-chloro-1-(4-fluorobenzyl)-N-((3    S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.    [2] A compound of formula (IA), or a pharmaceutically acceptable    salt thereof,

wherein

R¹ is hydrogen, halogen, cyano, C₁₋₄alkyl or C₁₋₄alkoxy;

R² is hydrogen;

p is 1 or 2 and each R⁴ is independently selected from halogen,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy.

[3] A compound of formula (TB), or a pharmaceutically acceptable saltthereof,

wherein

R¹ is hydrogen, halogen, C₁₋₄alkyl or C₁₋₄alkoxy;

R² is hydrogen;

R^(4a) is hydrogen or halogen;

R^(4b) is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl orC₁₋₄haloalkoxy;

R^(4c) is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄haloalkyl; and

R^(4d) is hydrogen or halogen,

wherein at least one of R^(4a), R^(4b), R^(4c) and R^(4d) is other thanhydrogen and no more than two of R^(4a), R^(4b), R^(4c) and R^(4d) arehydrogen.

[4] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[5] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[6] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[7] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[8] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[9] A compound according to [3] or a pharmaceutically acceptable saltthereof, which isN-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[10] A compound according to [3] or a pharmaceutically acceptable saltthereof, which is1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

[11] A compound according to any one of [1] to [10] or apharmaceutically acceptable salt thereof, for use in positive allostericmodulation of muscarinic receptor mAChR M1.

[12] A compound according to any one of [1] to [10] or apharmaceutically acceptable salt thereof, for use as a cognitiveimpairment improving agent in Alzheimer-type dementia (AD).

[13] A method for symptomatic treatment of cognitive impairment inAlzheimer-type dementia (AD) involving administering to a human subjectin need thereof a therapeutically effective amount of a compoundaccording to any one of [1] to [10] or a pharmaceutically acceptablesalt thereof.[14] A compound according to any one of [1] to [10] or apharmaceutically acceptable salt thereof, for use as a cognitiveimpairment improving agent in dementia with Lewy bodies (DLB).[15] A method for symptomatic treatment of cognitive impairment indementia with Lewy bodies (DLB) involving administering to a humansubject in need thereof a therapeutically effective amount of a compoundaccording to any one of [1] to [10] or a pharmaceutically acceptablesalt thereof.[16] A pharmaceutical composition comprising the compound according toany one of [1] to [10] or a pharmaceutically acceptable salt thereof, asan active ingredient in association with a pharmaceutically acceptablecarrier.

DESCRIPTION OF THE INVENTION

The compounds of the present invention belong to a group of compounds ofgeneral formula (I), or a pharmaceutically acceptable salt thereof,

wherein

Ring A is a non-aromatic C₅₋₈ carbocyclic group or a non-aromatic 5 to8-membered heterocyclic group, wherein Ring A may be optionallysubstituted with one or more substituents independently selected fromSubstituent Group α;

R¹ is hydrogen, halogen, cyano, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl or C₁₋₆ haloalkoxy;

R² is hydrogen, halogen, cyano, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl or C₁₋₆ haloalkoxy;

Ring B is phenyl or a 5 to 6-membered heteroaryl group;

n is 0 or 1;

R³ is phenyl or a 5 to 6-membered heteroaryl group, which phenyl orheteroaryl group may be optionally substituted with one or moresubstituents independently selected from Substituent Group α;

-   -   p is 0, 1, 2, 3 or 4;    -   each R⁴ independently is a group selected from Substituent Group        α;    -   each substituent selected from Substituent Group α is        independently halogen, hydroxyl, cyano, nitro, —NR⁵R⁵,        C(O)NR⁵R⁵, —C(O)OR⁵, —C(O)R⁵, —S(O)₂R⁵, —NR⁵S(O)₂R⁵, S(O)₂NR⁵R⁵,        —NR⁵C(O)R⁵, C₁₋₆alkyl and C₁₋₆alkoxy, which C₁₋₆alkyl and        C₁₋₆alkoxy are each optionally substituted by one or more        substituents independently selected from halogen, hydroxyl,        cyano, —NH₂, —NH(C₁₋₆alkyl) and —N(C₁₋₆alkyl)₂; and

each R⁵ independently is hydrogen or C₁₋₆alkyl.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the present descriptionencompasses all geometric and structural isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the description.

Certain compounds of formula (I) may exist in solvated, for examplehydrated, as well as unsolvated forms. It is to be understood that thepresent description encompasses all such solvated forms of compounds offormula (I).

In an embodiment of formula (I), Ring A is a C₅₋₇ cycloalkyl group or a6-membered heterocycloalkyl group, wherein Ring A is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, C₁₋₄alkyl and C₁₋₄hydroxyalkyl.

In one embodiment of formula (I), Ring A is a C₅₋₇ cycloalkyl groupoptionally substituted with one or more substituents independentlyselected from halogen, hydroxyl, C₁₋₄alkyl and C₁₋₄hydroxyalkyl.

In one embodiment of formula (I), Ring A is selected from:—

In one embodiment of formula (I), Ring A is a piperidin-4-yl orpiperidin-3-yl group, optionally substituted with one or moresubstituents independently selected from halogen, hydroxyl, C₁₋₄alkyland C₁₋₄hydroxyalkyl.

In an embodiment of formula (I), Ring A is selected from:—

In one embodiment of formula (I), Ring A is a tetrahydropyran-4-yl ortetrahydropyran-3-yl group optionally substituted with one or moresubstituents independently selected from halogen, hydroxyl, C₁₋₄alkyland C₁₋₄hydroxyalkyl. In an embodiment of formula (I), Ring A isselected from:—

In an embodiment of formula (I), Ring A is a group of formula (II),wherein R^(a) is hydroxyl, methyl or hydroxymethyl; and Z is CH₂, CF₂ orO

In an embodiment of formula (I), Ring A is

In an embodiment of formula (I), Ring A is

In an embodiment of formula (I), Ring A is

In an embodiment of formula (I), R¹ is hydrogen, halogen, cyano,C₁₋₄alkyl or C₁-4alkoxy.

In an embodiment of formula (I), R¹ is hydrogen, chloro, cyano, methylor methoxy.

In an embodiment of formula (I), R¹ is hydrogen, chloro, cyano ormethyl.

In an embodiment of formula (I), R² is hydrogen, halogen, cyano,C₁₋₄alkyl or C₁₋₄alkoxy.

In an embodiment of formula (I), R² is hydrogen, cyano, methyl ormethoxy.

In an embodiment of formula (I), R² is hydrogen, cyano or methyl.

In an embodiment of formula (I), n is 0.

In an embodiment of formula (I), p is 1 or 2 and each R⁴ isindependently selected from halogen, hydroxyl, cyano, —NH₂,—NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl andC₁₋₄ haloalkoxy.

In an embodiment of formula (I), Ring B is a phenyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl or pyrazol-4-ylgroup, wherein Ring B is optionally substituted with one or twosubstituents independently selected from halogen, hydroxyl, cyano, —NH₂,—NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl andC₁₋₄ haloalkoxy. In a further embodiment of formula (I), Ring B is aphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl,thiazol-4-yl or pyrazol-4-yl group, wherein Ring B is optionallysubstituted with one or two substituents independently selected fromfluoro, chloro, cyano, methyl, trifluoromethyl, methoxy andtrifluoromethoxy.

In one embodiment of formula (I), Ring B is a phenyl group optionallysubstituted with one or two substituents independently selected fromhalogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy. In a furtherembodiment, Ring B is a phenyl group optionally substituted with one ortwo substituents independently selected from fluoro, chloro, bromo,methyl, methoxy, trifluoromethyl and trifluoromethoxy.

In one embodiment of formula (I), Ring B is selected from:—

In one embodiment of formula (I), Ring B is a pyridin-2-yl, pyridin-3-ylor pyridin-4-yl group, wherein Ring B is optionally substituted with oneor two substituents independently selected from halogen, hydroxyl,cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄haloalkyl and C₁₋₄ haloalkoxy. In a further embodiment, Ring B is apyridin-2-yl, pyridin-3-yl or pyridin-4-yl group, wherein Ring B isoptionally substituted with one or two substituents independentlyselected from fluoro, chloro, cyano, methyl and methoxy.

In an embodiment of formula (I), Ring B is selected from:—

In one embodiment of formula (I), Ring B is a thiazol-2-yl, athiazol-4-yl or a pyrazol-4-yl group, any of which may be optionallysubstituted with one or two substituents independently selected fromhalogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is selected from:—

In an embodiment of formula (I), n is 1.

In an embodiment of formula (I), Ring B is a group of formula (III),

wherein R³ is a phenyl, pyridin-2-yl, pyridin-4-yl, pyrazol-1-yl,pyrazol-4-yl, imidazol-2-yl or imidazol-4-yl group, wherein R³ isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl),N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy;p is 0 or 1; and R⁴ is halogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl),N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl or C₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is a group of formula (III)wherein R³ is a phenyl group optionally substituted with one or moresubstituents independently selected from halogen, hydroxyl, cyano, —NH₂,—NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl andC₁₋₄ haloalkoxy; p is 0 or 1; and R⁴ is halogen hydroxyl, cyano, —NH₂,—NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl orC₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is:

In one embodiment of formula (I), Ring B is a group of formula (III)wherein R³ is a pyridin-4-yl or pyridin-2-yl group optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy; p is 0 or 1;and R⁴ is halogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl or C₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is selected from:—

In one embodiment of formula (I), Ring B is a group of formula (III)wherein R³ is a pyrazol-1-yl or pyrazol-4-yl group optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy; p is 0 or 1;and R⁴ is halogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl or C₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is selected from:—

In one embodiment of formula (I), Ring B is a group of formula (III)wherein R³ is an imidazol-2-yl or imidazol-4-yl group optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy; p is 0 or 1;and R⁴ is halogen, hydroxyl, cyano, —NH₂, —NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl or C₁₋₄ haloalkoxy.

In one embodiment of formula (I), Ring B is selected from:—

In one aspect, the present invention provides a compound orpharmaceutically acceptable salt which is

-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-((5-fluoropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,4-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(trans-2-hydroxycycloheptyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-cyano-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-5-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-(6-methylpyridin-2-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-(2-methylpyridin-4-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(trans-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (S)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (S)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   (R)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-bromobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxy-3-methylbenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-((6-cyanopyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-((5-chloropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3-fluoro-4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(3-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-fluorobenzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-1-(4-fluorobenzyl)-N-((3    S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluoro-3-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3,4-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-4-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(3,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2-fluoro-3-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxy-3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;    or-   N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound offormula (IA), or a pharmaceutically acceptable salt thereof,

wherein

R¹ is hydrogen, halogen, cyano, C₁₋₄alkyl or C₁₋₄alkoxy;

R² is hydrogen;

-   -   p is 1 or 2 and each R⁴ is independently selected from halogen,        C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy.

In one embodiment, the present invention provides a compound of formula(IA), or a pharmaceutically acceptable salt thereof, wherein R¹ ishydrogen, chloro, methyl or methoxy; R² is hydrogen; p is 1 or 2 andeach R⁴ is independently selected from fluoro, chloro, bromo, methyl,methoxy, trifluoromethyl and trifluoromethoxy.

In a further aspect, the present invention provides a compound offormula (IB), or a pharmaceutically acceptable salt thereof,

wherein

R¹ is hydrogen, halogen, C₁₋₄alkyl or C₁₋₄alkoxy;

R² is hydrogen;

R^(4a) is hydrogen or halogen;

R^(4b) is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl orC₁₋₄haloalkoxy;

R^(4c) is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄haloalkyl; and

R^(4d) is hydrogen or halogen,

wherein at least one of R^(4a), R^(4b), R^(4c) and R^(4d) is other thanhydrogen and no more than two of R^(4a), R^(4b), R^(4c) and R^(4d) arehydrogen.

In one embodiment, the present invention provides a compound of formula(TB), or a pharmaceutically acceptable salt thereof, wherein R¹ ishydrogen, chloro, methyl or methoxy; R² is hydrogen; R^(4a) is hydrogenor fluoro; R^(4b) is hydrogen, fluoro, chloro, bromo, methyl, methoxy,trifluoromethyl or trifluoromethoxy; R^(4c) is hydrogen, fluoro, methyl,methoxy or trifluoromethyl; and R^(4d) is hydrogen or fluoro; wherein atleast one of R^(4a), R^(4b), R^(4c) and R^(4d) is other than hydrogenand no more than two of R^(4a), R^(4b), R^(4c) and R^(4d) are hydrogen.

In a further aspect, the present invention provides a compound offormula (IB) or a pharmaceutically acceptable salt thereof, which is

-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;    or-   1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In a further aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, which is

-   1-(3-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

An embodiment of formula (I) provides a compound of formula (IC), or apharmaceutically acceptable salt thereof,

wherein

R¹ is hydrogen, halogen, cyano, C₁₋₄alkyl or C₁₋₄alkoxy;

R² is hydrogen;

p is 1 or 2 and each R⁴ is independently selected from halogen,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy.

In an embodiment of formula (IC), the compound or pharmaceuticallyacceptable salt thereof isN-((1S,2S)-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

In an embodiment of formula (IC), the compound or pharmaceuticallyacceptable salt thereof isN-((1R,2R)-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

As used herein, the term “non-aromatic C₅₋₈ carbocyclic group” denotes anon-aromatic ring system having 5 to 8 ring carbon atoms, includingcycloalkyl rings, partially saturated rings and bridged rings. The term“cycloalkyl” denotes saturated carbocyclic rings. Examples of“cycloalkyl” rings include cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “non-aromatic 5-8-membered heterocyclic group”denotes a non-aromatic ring system having 5 to 8 ring atoms wherein atleast one ring atom is selected from nitrogen, oxygen and sulphur,including heterocycloalkyl rings and partially saturated rings. The term“heterocycloalkyl” denotes saturated heterocyclic rings. Examples of a“5 to 8-membered non-aromatic heterocyclic group”, include pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl groups.

As used herein, the term “heteroaryl” denotes aromatic rings having 5 to6 ring atoms wherein at least one ring atom is selected from nitrogen,oxygen and sulphur. Examples of “heteroaryl” groups include furanyl,thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isooxazolyl,thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl groups.

As used herein, the term “C₁₋₆alkyl” refers to an alkyl group having 1to 6 carbon atoms. Examples of the group include linear and branchedalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,1-methylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl,1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl,1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl and 3-methylpentyl.

As used herein, the term ‘C₁₋₆ haloalkyl’ denotes a C₁₋₆alkyl groupsubstituted with one or more halogen atoms wherein each halogen isindependently selected from fluorine, chlorine, bromine and iodine.Examples of C₁₋₆ haloalkyl groups include CF₃ (trifluoromethyl), CHF₂(difluoromethyl), CH₂F (monofluoromethyl), CH₂CF₃, CH₂CHF₂ and CH₂CH₂F.

As used herein, the term “C₁₋₆alkoxy” refers to a group containing analkyl group bonded to an oxygen atom. Examples of the group includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, n-pentoxy, isopentoxy, sec-pentoxy, t-pentoxy, n-hexyloxy,isohexyloxy, 1,2-dimethylpropoxy, 2-ethylpropoxy,1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy,1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy,2-ethylbutoxy, 1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy andhexyloxy. Examples of a “C₁₋₆haloalkoxy” group include —OCHF₂(difluoromethoxy) and —OCF₃ (trifluoromethoxy).

As used herein, the term ‘C₁₋₄ hydroxyalkyl’ denotes a C₁₋₄alkyl groupsubstituted with one to three hydroxyl groups. Examples of C₁₋₄hydroxyalkyl groups include —CH₂OH (hydroxymethyl).

In the context of the present specification, where it is stated that agroup is optionally substituted with one or more substituents, the groupmay be substituted or unsubstituted. When substituted the group may forexample be substituted with 1, 2 or 3 substituents.

In the present description, although crystal polymorphs of a compound offormula (I) may be present, the compound is similarly not limitedthereto and may be present as a single crystal form or a mixture ofsingle crystal forms. The compound may be an anhydride or a hydrate. Anyof these forms are included in the scope of formula (I) and the presentinvention.

The present description also includes isotopically-labelled compounds,which are identical to the compounds of formula (I), except that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of thedescription include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine, phosphorous, chlorine, technetium and iodine, such as ²H, ³H,¹¹C, ¹⁴C, ¹³N, ¹⁵O, ¹⁸F, ³²P, ^(99m)Tc, ¹²³I and ¹³¹I.

Compounds of the present description and pharmaceutically acceptablederivatives (e.g. salts) of said compounds that contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of the present description Isotopically-labelled compounds ofthe present description for example those into which radioactiveisotopes such as ³H and/or ¹⁴C are incorporated, may be useful in drugand/or substrate tissue distribution assays. ³H and ¹⁴C are considereduseful due to their ease of preparation and detectability. ¹¹C, ¹⁵O and¹⁸F isotopes are considered useful in PET (positron emissiontomography), and ^(99m)Tc, ¹²³I and 131I isotopes are considered usefulin SPECT (single photon emission computerized tomography), all useful inbrain imaging. Substitution with heavier isotopes such as ²H can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, are considered useful in some circumstances.Isotopically labeled compounds of formula (I) of this description cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples below, by substituting a readilyavailable isotopically labelled reagent for a non-isotopically labelledreagent.

The 4-azaindole derivative of formula (I) according to the presentdescription may be a pharmaceutically acceptable salt. Pharmaceuticallyacceptable salts include those described by Berge, Bighley andMonkhouse, J. Pharm. Sci., 1977, 66, 1-19. Specific examples of thepharmaceutically acceptable salt include inorganic acid salts (such assulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates,hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), organiccarboxylates (such as acetates, oxalates, maleates, tartrates,fumarates, citrates, malonates and lactates), organic sulfonates (suchas methanesulfonates, trifluoromethanesulfonates, ethanesulfonates,benzenesulfonates, toluenesulfonates and camphorsulfonates), amino acidsalts (such as aspartates and glutamates), quaternary amine salts,alkali metal salts (such as sodium salts and potassium salts) and alkaliearth metal salts (such as magnesium salts and calcium salts).

The compound of formula (I) according to the present description can beconverted to a pharmaceutically acceptable salt by a conventional methodwhere necessary. The salt can be prepared by a method in which methodstypically used in the field of organic synthetic chemistry and the likeare appropriately combined. Specific examples of the method includeneutralization titration of a free solution of the compound of thepresent description with an acid solution.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use intherapy.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inpositive allosteric modulation of mAChR M1.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, which haspotential use for treating or preventing a neurodegenerative disease.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, which haspotential use for treating or preventing Alzheimer-type dementia (AD).

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as acognitive impairment improving agent in Alzheimer-type dementia (AD).

In one embodiment, the present description provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament which has potential use for thetreatment or prevention of Alzheimer-type dementia (AD).

In one embodiment, the present description provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for use as a cognitive impairmentimproving agent in Alzheimer-type dementia (AD).

In one embodiment, the description provides a method that has potentialfor use in treating or preventing Alzheimer-type dementia (AD) involvingadministering to a human subject in need thereof a therapeutically orprophylactically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In one embodiment, the description provides a method for symptomatictreatment of cognitive impairment in Alzheimer-type dementia (AD)involving administering to a human subject in need thereof atherapeutically amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, which haspotential use for treating or preventing dementia with Lewy bodies(DLB).

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as acognitive impairment improving agent in dementia with Lewy bodies (DLB).

In one embodiment, the present description provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament which has potential use for thetreatment or prevention of dementia with Lewy bodies (DLB).

In one embodiment, the present description provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for use as a cognitive impairmentimproving agent in dementia with Lewy bodies (DLB).

In one embodiment, the present description provides a method that haspotential for use in treating or preventing dementia with Lewy bodies(DLB) involving administering to a human subject in need thereof atherapeutically or prophylactically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment, the present description provides a method forsymptomatic treatment of cognitive impairment in dementia with Lewybodies (DLB) involving administering to a human subject in need thereofa therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In one embodiment, the present description provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, which haspotential for use in treating or preventing schizophrenia, including thecognitive deficits associated with schizophrenia.

In another embodiment, the present description provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament which has potential use for thetreatment or prevention of schizophrenia, including the cognitivedeficits associated with schizophrenia.

In a further embodiment, the present description provides a method thathas potential use for treating or preventing schizophrenia, includingthe cognitive deficits associated with schizophrenia, involvingadministering to a human subject in need thereof a therapeutically orprophylactically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In the context of the present specification “effective amount” means anamount sufficient to cause a benefit to the subject or at least to causea change in the subject's condition.

A further aspect of the description provides a pharmaceuticalcomposition comprising a compound of formula (I) as defined above, or apharmaceutically acceptable salt thereof, as active ingredient inassociation with a pharmaceutically acceptable carrier. The compositionmay be in any suitable form, depending on the intended method ofadministration. It may for example be in the form of a tablet, capsuleor liquid for oral administration, or of a solution or suspension foradministration parenterally.

The 4-azaindole derivative or pharmaceutically acceptable salt thereofaccording to the present description may be formulated by a conventionalmethod. Preferable examples of the dosage form include tablets, coatedtablets such as film tablets and sugar-coated tablets, fine granules,granules, powders, capsules, syrups, troches, inhalants, suppositories,injections, ointments, eye drops, nasal drops, ear drops, cataplasms andlotions.

These solid preparations such as tablets, capsules, granules and powderscan contain generally 0.01 to 100 wt %, and preferably 0.1 to 100 wt %of the 4-azaindole derivative or pharmaceutically acceptable saltthereof according to the present description as an active ingredient.

The active ingredient is formulated by blending ingredients generallyused as materials for a pharmaceutical preparation and adding anexcipient, a disintegrant, a binder, a lubricant, a colorant and acorrective typically used, and adding a stabilizer, an emulsifier, anabsorbefacient, a surfactant, a pH adjuster, a preservative and anantioxidant where necessary, for example, using a conventional method.Examples of such ingredients include animal and vegetable oils such assoybean oil, beef tallow and synthetic glyceride; hydrocarbons such asliquid paraffin, squalane and solid paraffin; ester oils such asoctyldodecyl myristate and isopropyl myristate; higher alcohols such ascetostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil;surfactants such as polyoxyethylene fatty acid ester, sorbitan fattyacid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fattyacid ester, polyoxyethylene hydrogenated castor oil and apolyoxyethylene-polyoxypropylene block copolymer; water-soluble polymerssuch as hydroxyethylcellulose, polyacrylic acid, a carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone and methylcellulose; loweralcohols such as ethanol and isopropanol; polyhydric alcohols such asglycerol, propylene glycol, dipropylene glycol and sorbitol; sugars suchas glucose and sucrose; inorganic powders such as silicic anhydride,magnesium aluminum silicate and aluminum silicate; and purified water.Examples of the excipient used include lactose, corn starch, saccharose,glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.Examples of the binder used include polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin,shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene blockcopolymer and meglumine. Examples of the disintegrant used includestarch, agar, gelatin powder, crystalline cellulose, calcium carbonate,sodium bicarbonate, calcium citrate, dextrin, pectin andcarboxymethylcellulose calcium. Examples of the lubricant used includemagnesium stearate, talc, polyethylene glycol, silica and hydrogenatedvegetable oil. Examples of the colorant used include those permitted tobe added to pharmaceuticals. Examples of the corrective used includecocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder.Obviously, the ingredients are not limited to the above additiveingredients.

For example, an oral preparation is prepared by adding the 4-azaindolederivative or pharmaceutically acceptable salt thereof according to thepresent description as an active ingredient, an excipient and, wherenecessary, a binder, a disintegrant, a lubricant, a colorant, acorrective and the like, and then forming the mixture into powder, finegranules, granules, tablets, coated tablets, capsules or the like by aconventional method. Obviously, tablets or granules may be appropriatelycoated, for example, sugar coated, where necessary.

For example, a syrup or an injection preparation is prepared by adding apH adjuster, a solubilizer, an isotonizing agent and the like, and asolubilizing agent, a stabilizer and the like where necessary by aconventional method. The injection may be a previously preparedsolution, or may be powder itself or powder containing a suitableadditive, which is dissolved before use. The injection can containusually 0.01 to 100 wt %, and preferably 0.1 to 100 wt % of the activeingredient. Further, a liquid preparation for oral administration suchas a suspension or a syrup can contain usually 0.01 to 100 wt %, andpreferably 0.1 to 100 wt % of the active ingredient.

For example, an external preparation can be prepared by any conventionalmethod without specific limitations. As a base material, any of variousmaterials usually used for a pharmaceutical, a quasi drug, a cosmetic orthe like can be used. Examples of the base material include materialssuch as animal and vegetable oils, mineral oils, ester oils, waxes,higher alcohols, fatty acids, silicone oils, surfactants, phospholipids,alcohols, polyhydric alcohols, water-soluble polymers, clay minerals andpurified water. A pH adjuster, an antioxidant, a chelator, apreservative and fungicide, a colorant, a flavor or the like can beadded where necessary. Further, ingredients such as an ingredient havinga differentiation inducing effect, a blood flow enhancer, a bactericide,an antiphlogistic, a cell activator, vitamin, amino acid, a humectantand a keratolytic agent can be blended where necessary.

The dose of the 4-azaindole derivative or pharmaceutically acceptablesalt thereof according to the present descriptionvaries according to thedegree of symptoms, age, sex, body weight, mode of administration, typeof salt and specific type of disease, for example. Typically, the activeingredient is orally administered to an adult at about 30 μg to 10 g,preferably 100 μg to 5 g, and more preferably 100 μg to 1 g per day, oris administered to an adult by injection at about 30 μg to 1 g,preferably 100 μg to 500 mg, and more preferably 100 μg to 300 mg perday, in one or several doses, respectively.

Compounds of formula (I) may be used in combination with othertherapeutic agents, for example medicaments claimed to be useful aseither disease modifying or symptomatic treatments of a neurologicaldisorder such as Alzheimer-type dementia (AD) or schizophrenia. Thus, ina further aspect, the present description provides a pharmaceuticalproduct comprising, in combination, a first active ingredient which is acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further active ingredient useful in treating aneurological disorder such as Alzheimer-type dementia (AD) orschizophrenia. In one embodiment of the description, theneurodegenerative neurological disorder is Alzheimer-type dementia (AD).Suitable examples of such further active ingredients may be symptomaticagents, for example M4 agonists or positive allosteric modulators(PAMs), acetylcholinesterase inhibitors (such astetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), NMDAreceptor antagonists, nicotinic receptor agonists or allostericmodulators (such as α7 agonists or allosteric modulators or α4β2agonists or allosteric modulators), PPAR agonists (such as PPARγagonists), beta-site amyloid-β precursor protein cleavage enzyme 1(hereinafter referred to as BACE1 or beta-secretase) inhibitors 5-HT4receptor agonists or partial agonists, histamine H3 antagonists, 5-HT6receptor antagonists or 5HT1A receptor ligands and, 5-HT2A antagonists,5-HT7 antagonists, D1 agonists or PAMs, D2 antagonists, D4 agonists orPAMs, D5 agonists or PAMs, GABA-A α5 inverse agonists or negativeallosteric modulators (NAMs), GABA-A α2/3 agonists or PAMs, mGluR2inverse agonists or negative allosteric modulators, mGluR5 positiveallosteric modulators, PDE 1 inhibitors, PDE 2 inhibitors, PDE 4inhibitors, PDE 5 inhibitors, PDE 9 inhibitors, PDE 10 inhibitors, GlyT1inhibitors, DAAO inhibitors, ASC1 inhibitors, AMPA modulators, SIRT1activators or inhibitors, AT4 antagonists, GalR1 antagonists, GalR3ligands, adenosine A1 antagonists, adenosine A2a antagonists, α2Aantagonists or agonists, selective and unselective norepinephrinereuptake inhibitors (SNRIs), or potential disease modifying agents suchas gamma secretase inhibitors or modulators, alpha secretase activatorsor modulators, amyloid aggregation inhibitors, amyloid antibodies, tauaggregation inhibitors or tau phosphorylation/kinase inhibitors, taudephosphorylation/phosphatase activators, mitogen-activated proteinkinase kinase 4 (MKK4/MEK4/MAP2K4) inhibitors, c-Jun N-terminal kinase(JNK) inhibitors, casein kinase inhibitors, MK2 (mitogen activatedprotein kinase-activated protein kinase 2) inhibitors, MARK (microtubuleaffinity regulating kinase) inhibitors, CDKS (cyclin dependent kinase 5)inhibitors, GSK-3 (glycogen synthase kinase-3) inhibitors andtau-tubulin kinase-1 (TTBK1) inhibitors. Further examples of such othertherapeutic agents may be calcium channel blockers, HMG-CoA(3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) andlipid lowering agents, NGF (nerve growth factor) mimics, antioxidants,GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE(insulin degrading enzyme) activators, melatonin MT1 and/or MT2agonists, TLX/NR2E1 (tailless X receptor) ligands, GluR1 ligands, RAGE(receptor for advanced glycation end-products) antagonists, EGFR(epidermal growth factor receptor) inhibitors, FPRL-1 (formylpeptide-like receptor-1) ligands, GABA antagonists, and MICAL (moleculeinteracting with casL) inhibitors, e.g. oxoreductase inhibitors, CB1antagonists/inverse agonists, non-steroidal anti-inflammatory drugs(NSAIDs), anti-inflammatory agents (for example agents that could beused to treat neuroinflammation either by enhancing or reducingneuroinflammation), amyloid precursor protein (APP) ligands,anti-amyloid vaccines and/or antibodies, agents that promote or enhanceamyloid efflux and/or clearance, histone deacetylase (HDAC) inhibitors,EP2 antagonists, 11-beta HSD1 (hydroxysteroid dehydrogenase) inhibitors,liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-relatedprotein (LRP) mimics and/or ligands and/or enhancers and/or inhibitors,butyryl cholinesterase inhibitors, kynurinic acid antagonists and/orinhibitors of kynurenine aminotransferease (KAT), orphanin FQ/nociceptin(NOP)/opioid-like receptor 1 (ORL1) antagonists, excitatory amino acidtransporter (EAAT) ligands (activators or inhibitors), and plasminogenactivator inhibitor-1 (PAI-1) inhibitors, niacin and/or GPR109 agonistsor PAMs in combination with cholesterol lowering agents and/or HMGCoAreductase inhibitors (statins), dimebolin or similar agents,antihistamines, metal binding/chelating agents, antibiotics, growthhormone secretagogues, cholesterol lowering agents, vitamin E,cholesterol absorption inhibitors, cholesterol efflux promoters and/oractivators, and insulin upregulating agents.

In one embodiment, the present description provides a pharmaceuticalproduct comprising, in combination, a first active ingredient which is acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further active ingredient useful in treatingAlzheimer-type dementia selected from:

-   -   cholinesterase inhibitors, e.g. donepezil, galantamine,        rivastigamine, tetrahydroaminoacridine and pharmaceutically        acceptable salts thereof,    -   NMDA receptor antagonists, e.g. memantine and pharmaceutically        acceptable salts thereof,    -   5-HT6 antagonists, e.g. SB-742457 and pharmaceutically        acceptable salts thereof, and    -   HMGCoA reductase inhibitors e.g. lovastatin, rosuvastatin,        atorvastatin, simvastatin, fluvastatin, pitavastatin,        pravastatin and pharmaceutically acceptable salts thereof.

In another embodiment, the present description provides a pharmaceuticalproduct comprising, in combination, a first active ingredient which is acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further active ingredient useful in treatingschizophrenia selected from:—

-   -   Antipsychotic drugs e.g. chlorpromazine, thioridazine,        mesoridazine, fluphenazine, perphanazine, prochlorperazine,        trifluoperazine, thiothixine, haloperidol, molindone, loxapine,        clozapine, olanzapine, risperidone, quetiapine, aripirazole,        ziprasidone, amisulpride and pharmaceutically acceptable salts        thereof, and    -   Drugs used as mood stabilisers e.g. lithium, valproic acid,        carbamazepine, lamotrigine, gabapentin, topiramate, tiagabine        and pharmaceutically acceptable salts thereof,

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations. Consequently, the pharmaceutical productmay, for example be a pharmaceutical composition comprising the firstand further active ingredients in admixture. Alternatively, thepharmaceutical product may for example comprise the first and furtheractive ingredients in separate pharmaceutical preparations suitable forsimultaneous, sequential or separate administration to a patient in needthereof.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the description.

When a compound of formula (I) or a pharmaceutically acceptable saltthereof is used in combination with a second therapeutic agent active,the dose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art.

Thus, an additional aspect of the description provides a method ofpreparation of a pharmaceutical composition, involving admixing at leastone compound of formula (I) as defined above, or a pharmaceuticallyacceptable salt thereof, with one or more pharmaceutically acceptableadjuvants, diluents or carriers and/or with one or more othertherapeutically or prophylactically active agents.

General Methods for preparing a compound of formula (I) or apharmaceutically acceptable salt thereof, according to the presentdescription, are described herein below.

It will be appreciated by those skilled in the art that when preparingcertain compounds of formula (I) it may be appropriate to modify thegeneral preparation methods by alternating the sequence of reactionsteps and/or incorporating additional steps to vary substituent groupson intermediate compounds. Moreover, it will also be recognised thatcompounds of formula (I) prepared according to the general preparationmethods may subsequently be converted to other compounds of formula (I)using known chemistry. It will also be appreciated by those skilled inthe art that in some instances certain functional groups such ashydroxyl, carboxyl or amino groups in starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus thefollowing preparation methods may involve at certain stages theincorporation of one or more protecting groups. The protection anddeprotection of functional groups is, for example, described in‘Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999) and ‘Protecting Groups’, P. J.Kocienski, Georg Thieme Verlag (1994), hereby known as references 1 and2. Many of the reaction schemes to make intermediates utilise chemistrythat will be known to those skilled in the art and can be found inreferences such as ‘Organic Chemistry’, 2nd edition, J. Clayden, N.Greeves and S. Warren, Oxford University Press (2012) and ‘March'sAdvanced Organic Chemistry’, 6th edition, J. March, Wiley-VCH (2007),hereby known as references 3 and 4. Moreover, it will also beappreciated by those skilled in the art that preparation methodsinvolving the reaction of a carboxyl group may in certain instances beconducted using an equivalent alkyl ester or acid chloride.

The choice of solvent used in the steps described in the generalpreparation methods may vary according to the specific reagents used.Unless otherwise stated the choice of solvent is not particularlylimited insofar as it does not inhibit the reaction, allows the reagentsto be dissolved therein to a certain extent, and is inert during thereaction.

General Preparation Method:

Scheme 1

General Preparation Method A is a method for preparing a compound offormula (I) according to the present description from a compound A-(1)as a raw material through multiple steps of Step A-(i) to Step A-(v), asdepicted in scheme 1. In scheme 1, RingA, RingB, R¹, R², R³R⁴, n and pare as defined above in respect of compounds of formula (I). PG is asuitable protecting group for nitrogen, such as Boc, CBz orphenylsulfone for example. LG is a suitable halogen leaving group, suchas F, Cl, Br, I. Compounds of formula A-(1) are either commerciallyavailable, may be prepared by literature methods or may be prepared bymethods known to those skilled in the art.

Step A-(i):

This is a step of obtaining a compound A-(2) by substitution reaction ofa suitable halogen into a compound A-(1). The halogen introduced is notparticularly limited, insofar as it permits the desired reactivity inthe derivatives produced. Typically, bromine or iodine may beintroduced. Methods of introducing bromine include those described inUS)-20080009514A1 and WO201033980A2, and methods of introducing iodineinclude those described in WO2011/78984 A1, Bioorg. Med. Chem. Lett.2009, 24, 6935-6938, and Org. Bio. Chem. 2011, 14, 5129-5136.Alternatively, the reaction may be performed with iodine in the presenceof a suitable base.

The solvent used in this step varies according to starting material andthe reagent used. Examples of solvents include organic solvents, such asN—,N-dimethylformamide or N—,N-dimethylacetamide When a base is requiredthe choice of base used is not particularly limited. Examples of basesinclude inorganic bases, for example potassium hydroxide or sodiumhydroxide. The reaction time is not particularly limited and is usually0.5 to 72 hours, typically 0.5 to 5 hours. The reaction temperaturevaries according to the starting material, the reagent used and thelike, and is typically in the range of from 20° C. to 100° C.

Step A-(ii):

This is a step of protecting the aza-indole nitrogen in A-(2) togenerate A-(3). The protection and deprotection of functional groups is,for example, described in references 1 and 2. The protecting group usedin this step can be varied according to starting material, and is notparticularly limited insofar as the protecting group does not interferewith reactions to which compound A-(3) and any future protectedderivatives will be subjected. Specifically, when PG=Boc, the reactioncan be carried out using di-tert butyl dicarbonate and a suitable base.

The solvent used in this step varies according to starting material andthe reagent used. Examples of solvents include organic solvents, such asdichloromethane or tetrahydrofuran. When a base is required the choiceof base is not particularly limited. Examples of bases include organicbases, such as triethylamine or DIPEA, or inorganic salts, for examplesodium bicarbonate or potassium carbonate. The reaction time is notparticularly limited and is usually 0.5 to 72 hours, typically 0.5 to 5hours. The reaction temperature varies according to the startingmaterial, the reagent used and the like, and is typically in the rangeof from 20° C. to 100° C.

Step A-(iii):

This step is a step of obtaining compound A-(4) by the reaction ofcompound A-(3) and an amine compound a-(iii) (RingA-NH₂) utilizing atransition metal-mediated coupling reaction in the presence of carbonmonoxide and a suitable base.

Those skilled in the art will appreciate that this transformation can beaccomplished by a range of conditions. For example compound A-(3) can betransformed to A-(4) using a transition metal catalyst, for example apalladium catalyst such as palladium (II) acetate and Xantphos™ in a 1:2ratio. Alternatively, a wide variety of other related transition metalcatalysts may also be suitable for this transformation, for exampletetrakis(triphenylphosphine)palladium (O),[1,1′-bis(diphenylphosphino)ferrocene] palladium (II) dichloride,bis(triphenylphosphino) palladium (II) dichloride. The amount of theorganometallic catalyst used is about 0.001 to 0.5 equivalent withrespect to the raw material. Those skilled in the art will understandthat many such catalysts are known and that many of such catalysts arecapable of effecting this transformation and that the substrate A-(3) orthe coupling partner may dictate which catalyst can or cannot be used.

The aforementioned transition metal mediated coupling reactions requirean amine compound a-(iii) to act as the coupling partner. Such aminesare not particularly limited. The amount of the coupling partner used isnot particularly limited and is usually 1 to 5 equivalents with respectto the compound A-(3). Amine compounds a-(iii) are either commerciallyavailable, may be prepared by literature methods or may be prepared bymethods known to those skilled in the art.

In addition to the aforementioned catalyst and reaction partner, thesetransition-metal mediated reactions require a solvent and often a baseor salt is required to be present. The solvent used in this reaction isnot particularly limited insofar as it does not inhibit the reaction.Examples of the solvent include benzene, toluene, N,N-dimethylformamide,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and the like andmixtures thereof. Such a base or salt is not particularly limited.Examples of the base or salt include bases or salts such as sodiumcarbonate, potassium carbonate, barium hydroxide, cesium carbonate,potassium phosphate, cesium fluoride, potassium fluoride and solutionsthereof, and organic bases, such as triethylamine,N,N-diisopropylethylamine.

The reaction can be carried out in an atmosphere of carbon monoxide withpressure typically ranging from 20 to 100 p.s.i.

The reaction may be conducted at various temperatures, for example fromroom temperature to solvent reflux temperature. The reaction time is notparticularly limited and is usually 0.5 to 48 hours, typically 0.5 to 24hours.

Step A-(iv):

This is a step of obtaining compound A-(5) from compound A-(4) byremoval of the protecting group.

Suitable conditions to convert A-(4) to A-(5) include those described inreferences 1 and 2. For example, a) when PG=Boc, A-(4) may be convertedto A-(5) by treating with an acid e.g. TFA or HCl in ether or dioxane;b) when PG=Cbz, A-(4) may be converted to A-(5) by hydrogenation in thepresence of a palladium catalyst in a suitable solvent; and c) whenPG=Teoc, A-(4) may be converted to A-(5) by treatment with fluoride in asuitable solvent.

Step A-(v):

This is a step of obtaining a compound (I) by substitution reaction ofan alkyl halide of formula a-(v) to the compound A-(5) in the presenceof a suitable base. In the compound of formula a-(v), X may for examplebe Cl or Br.

The reaction in this step can be performed under many conditions knownto those skilled in the art, such as those reported in WO2004/31188 A1,WO2010/80474 A1, WO2012/88469 A1 or WO2009/32125 A1, for example.

Alkyl halides of formula a-(v) are either commercially available, may beprepared by literature methods or may be prepared by methods known tothose skilled in the art.

The solvent used in this step varies according to starting material andthe reagent used. Examples of solvents include organic solvents, such astetrahydrofuran mixed with water or N—,N-dimethylformamide in theabsence of water. The base used is not particularly limited insofar asit does not react with the alkyl halide. Examples of bases includeinorganic bases, for example cesium carbonate or potassium hydroxide.The reaction time is not particularly limited and is usually 0.5 to 72hours, typically 0.5 to 5 hours. The reaction temperature variesaccording to the starting material, the reagent used and the like, andis typically in the range of from 20° C. to 100° C.

The present invention will be described more specifically below withreference to the following illustrative Examples. However, the presentinvention is not limited thereto. The abbreviations used in Examples areconventional abbreviations known to a person skilled in the art. Someabbreviations are listed below:

-   DCM—Dichloromethane-   TEA—Triethylamine-   EtOAc—Ethyl Acetate-   BOP—(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   DMF—N—, N-dimethylformamide-   HOBt—Hydroxybenzotriazole-   THF—Tetrahydrofuran-   Pd(PPh₃)₄—Palladium-tetrakis(triphenylphosphine)-   rt—room temperature-   TFA—Trifluoroacetic acid-   mCPBA—meta-chloro perbenzoic acid-   DBU—1,8-Diazabicyclo[5.4.0]undec-7-ene-   MeCN—Acetonitrile-   dppf—1,1′-Bis(diphenylphosphino)ferrocene-   Pd(OAc)₂—Palladium (II) Acetate-   XantPhos—4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene-   DMSO—dimethylsulfoxide-   AIBN—2,2′-Azobis(2-methylpropionitrile)-   HATU—1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   DMAP—4-dimethylamino pyridine-   CDCl₃—deutero-chloroform-   prep.—preparatory-   CD₃OD—deutero-methanol-   MeOH—Methanol-   LC-MS—Liquid Chromatography-Mass Spectrometry-   NMR—Nuclaer Magnetic Resonance-   TBAF—tetra-n-butylammonium fluoride

¹H NMR spectra were recorded on a Bruker AV 400, a Bruker Avance III 400spectrometer operating at a (reported) frequency of 400 MHz, a BrukerAvance III 600 series operating at a (reported) frequency of 600 MHz, orVarian MERCURYplus 400 operating at a (reported) frequency of 400 MHz.Chemical shifts in proton nuclear magnetic resonance spectra arerecorded in δ units (ppm) relative to tetramethylsilane and couplingconstants (J) are recorded in Hertz (Hz). Chemical shift and couplingconstants were analyzed using ACD/Spectrus Processor (Fujitsu) Patternsare designated as s: singlet, d: doublet, t; triplet, br; broad, m;multiplet. Chemical names were generated from chemical structures usingChemBioDraw Ultra 11.0 and 12.0 or E-notebook version 12 (PerkinElmer)

Intermediate Compounds

Intermediate 4: Synthesis ofN-((1S,2S)-2-Hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 1: 3-Iodo-1H-pyrrolo[3,2-b]pyridine

To a mixture of 1H-pyrrolo[3,2-b]pyridine (Purchased from Combi BlocksInc.), (5 g) and DMF (100 mL) stirred under nitrogen at room temperaturewas added potassium hydroxide (9.02 g) followed by iodine (12.89 g) andthe resulting mixture was stirred at room temperature for 1 h 5 min.,then poured onto a mixture of Na₂S₂O₅.5H₂O (4.25 g), water (635 mL), and28-30% ammonium hydroxide (43 mL). The resultant mixture was cooled inan ice bath for 20 min, and the precipitate thus produced was filteredand washed with ice water then dried under vacuum to give the titlecompound (9.18 g).

LCMS: m/z 245.39 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 7.17 (dd, J=8.1, 4.5 Hz, 1H) 7.72-7.87 (m,2H) 8.38 (d, J=4.4 Hz, 1H) 11.74 (br. s., 1H)

(2) Intermediate 2: tert-Butyl3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 1), (6g), 4-Dimethylaminopyridine (0.390 g) and DCM (60.0 mL) stirred at roomtemperature under nitrogen was added dropwise a solution ofdi-t-butyldicarbonate (8.05 g) in DCM (60 mL) and the reaction wasstirred overnight at rt, then concentrated under vacuum. The residue waspurified by column chromatography (normal phase, 100 g, Biotage SNAPcartridge KP-Sil, 50 mL per min, gradient 0% to 30% EtOAc in n-hexane)to give the desired compound (8.21 g).

LCMS: m/z 345.45 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.69 (s, 9H) 7.31 (dd, J=8.3, 4.8 Hz, 1H)7.99 (s, 1H) 8.33-8.45 (m, 1H) 8.64 (dd, J=4.7, 1.2 Hz, 1H)

(3) Intermediate 3: tert-Butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Intermediate2), (8 g), (1S,2S)-2-aminocyclohexanol hydrochloride (Purchased fromGreenchempharm Inc.), (5.29 g), palladium (II) acetate (0.157 g),XantPhos (0.807 g), toluene (210 mL) and TEA (9.72 mL) were placed in a500 mL three necked flask with a CO balloon and condenser attached. Thereaction mixture was purged with CO then heated to 80° C. over aweekend. The reaction was cooled to rt and poured onto EtOAc, theremaining solid in the reaction flask was sonicated with a small amountof THF and the slurry added to the EtOAc organic phases. The combinedorganic phases were washed with water (2×) then brine and the combinedaqueous phases extracted with EtOAc (1×). The combined organic extractswere dried (MgSO₄), filtered and evaporated under vacuum to give thedesired compound (8.72 g), which was taken on crude.

LCMS: m/z 360.60 [M+H]⁺.

(4) Intermediate 4:N-((1S,2S)-2-Hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 3), (8.35 g) in DCM (100 mL) stirred at rt under nitrogenwas added TFA (50 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was purified bycolumn chromatography (normal phase, 375 g, Biotage SNAP cartridgeKP-NH, 100 mL per min, gradient 0% to 100% EtOAc in n-hexane, then 0-20%MeOH in EtOAc) to give the desired compound (5.64 g).

LCMS: m/z 260.51 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.18-1.41 (m, 4H) 1.51-1.72 (m, 2H) 1.88(d, J=9.1 Hz, 1H) 2.04 (d, J=9.4 Hz, 1H) 3.24-3.48 (m, 1H) 3.65-3.80 (m,1H) 4.79 (br. s., 1H) 7.24 (dd, J=8.1, 4.7 Hz, 1H) 7.91 (d, J=8.2 Hz,1H) 8.15 (s, 1H) 8.46 (d, J=4.5 Hz, 1H) 8.81 (d, J=7.5 Hz, 1H).

Intermediate 13: Synthesis ofN-((1S,2S)-2-Hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(1) Intermediate 5: 1H-Pyrrolo[3,2-b]pyridine 4-oxide

To a mixture of 1H-pyrrolo[3,2-b]pyridine (25 g) in DCM (885 mL) stirredat rt under nitrogen was added a suspension of m-chloroperbenzoic acid(54.8 g) in DCM (885 mL). The reaction was stirred at rt overnight, atwhich point LC-MS indicated completion. The crude reaction was filteredand the residue was stirred as a slurry in Et₂O (1 L) for 30 min, thenfiltered. The residue was again stirred as a slurry in 1 L Et₂O andfiltered. The residue was dried under vacuum to give the title compound,(27.9 g) which still contained traces of m-chlorobenzoic acid, but wasused without further purification.

LCMS: m/z 135.43 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) ppm 6.87 (d, J=3.2 Hz, 1H) 7.23-7.32 (m, 1H)7.69 (s, 1H) 7.77 (d, J=8.3 Hz, 1H) 8.21 (d, J=6.4 Hz, 1H).

(2) Intermediate 6: 7-Chloro-1H-pyrrolo[3,2-b]pyridine

To a mixture of 1H-pyrrolo[3,2-b]pyridine 4-oxide (Intermediate 5),(27.9 g) stirred at rt under nitrogen was added phosphorus oxychloride(85 mL) and the resulting mixture was heated under nitrogen at 80° C.overnight to give a dark solution, at which point LC-MS indicatedcompletion. The reaction was cooled to rt and added slowly to ice-cold5N NaOH (300 mL) with vigorous stirring. Water (50 mL) was added and theresultant emulsion was filtered and washed with water to give a solidwhich was dried under suction then high vacuum and the crude materialwas taken on as such.

LCMS: m/z 153.36 [M+H]⁺.

(3) Intermediate 7:7-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine

To a mixture of 7-chloro-1H-pyrrolo[3,2-b]pyridine (Intermediate 6),(31.7 g) in DCM (1.23 L) stirred under nitrogen at rt was addedbenzenesulfonyl chloride (39.8 mL), tetrabutylammonium hydrogen sulfate(9.18 g) and 50% aq. NaOH (33.2 mL) and the reaction was stirred at rtovernight, at which point LC-MS indicated formation of the desiredproduct. Sat. aq. NaHCO₃, (500 mL) was added, the layers were separatedand the aqueous phase was extracted 2× with DCM, dried (MgSO₄), filteredand evaporated under vacuum. The residue was purified by columnchromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50mL per min, gradient 0% to 80% EtOAc in n-hexane) to give the desiredproduct (14.6 g).

LCMS: m/z 293.42 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 6.82 (d, J=3.9 Hz, 1H) 7.24-7.29 (m, 1H)7.50 (t, J=7.8 Hz, 2H) 7.55-7.67 (m, 1H) 7.81 (d, J=3.7 Hz, 1H)7.84-7.92 (m, 2H) 8.23 (d, J=8.8 Hz, 1H).

(4) Intermediate 8:7-Methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine

A mixture of 7-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 7), (16.6 g) and Pd(PPh₃)₄ (5 g) were de-aerated byplacing under high vacuum then purging with nitrogen (3×). To thesesolids was added THF (251 mL) then a 2M THF solution of methylzinc(II)chloride (56.7 mL). This mixture was heated to 90° C. for 2 h, at whichpoint LC-MS indicated full conversion to product. The reaction wascooled to rt and solvents were removed under reduced pressure. Theresidue was slurried in 500 mL diethyl ether for 30 min, and thesupernatant was removed and concentrated to reveal. The process wasrepeated 3× and supernatants were combined. The residue was partitionedbetween water (500 mL) and DCM (500 mL), layers were separated and theaqueous layer was extracted 3× with DCM. Combined organic phases werewashed with NaHCO₃ and brine. The combined ether supernatants weredissolved in DCM, washed with water, NaHCO₃ and brine. Organic phaseswere combined with those from the DCM extractions and the resultantproduct was taken on as such without further purification.

LCMS: m/z 273.53 [M+H+]⁺.

(5) Intermediate 9: 7-Methyl-1H-pyrrolo[3,2-b]pyridine

To a solution of 7-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 8), (15.44 g) in ethanol (1059 mL) stirred at rt was added10% aq. NaOH (100 mL) and the reaction was heated at 70° C. for 2 h, atwhich point LC-MS indicated disappearance of SM. The reaction was cooledto rt, reduced in vacuo, poured onto brine, extracted with EtOAc (3×),and evaporated under vacuum. The residue was purified by columnchromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mLper min, gradient 0% to 100% EtOAc in n-hexane) to yield the desiredproduct (3.75 g).

LCMS: m/z 133.45 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 2.55 (s, 3H) 6.74-6.79 (m, 1H) 6.96 (d,J=4.9 Hz, 1H) 7.45 (t, J=2.7 Hz, 1H) 8.38 (d, J=4.7 Hz, 1H) 8.77 (br.s., 1H).

(6) Intermediate 10: 3-Iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine

To a solution of 7-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate 9),(3.65 g) in THF (219 mL) stirred at rt under nitrogen was addedN-iodosuccinimide (6.83 g) and the reaction was stirred at rt undernitrogen overnight, at which point LC-MS indicated completion. Thereaction was then reduced in vacuo, dissolved in MeOH and loaded onto a20 g SCX-2 cartridge, washing with 5CV MeOH. The product was eluted bywashing with 5CV 2M NH₃/MeOH and the ammonia-containing fractions werecombined and reduced in vacuo to yield the desired compound. The MeOHfractions were combined and reduced in vacuo, dissolved in MeOH andloaded onto a fresh 20 g SCX-2 cartridge, washing with 5CV MeOH, theneluted with 5CV 2M NH₃/MeOH. The ammonia-containing fractions werecombined with those from the first SCX-2 cartridge and reduced in vacuoto yield the desired compound (5.756 g).

LCMS: m/z 259.41 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) ppm 2.58 (s, 3H) 7.07 (d, J=4.9 Hz, 1H) 7.65 (s,1H) 8.25 (d, J=4.7 Hz, 1H).

(7) Intermediate 11: tert-Butyl3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine (Intermediate10), (1.355 g) and 4-dimethylaminopyridine (83 mg) in DCM (12.84 mL)stirred at rt under nitrogen was added a solution ofdi-t-butyldicarbonate (1.719 g) in DCM (5 mL) dropwise and the reactionwas stirred overnight, at which point LC-MS indicated completion. Thereaction was reduced in vacuo and the residue was purified by columnchromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mLper min, gradient 0% to 20% EtOAc in n-hexane) to yield the desiredcompound (1.706 g).

LCMS: m/z 359.46 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.67 (s, 9H) 2.73 (s, 3H) 7.10 (d, J=4.8 Hz,1H) 7.95 (s, 1H) 8.49 (d, J=4.8 Hz, 1H).

(8) Intermediate 12: tert-Butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

(1S,2S)-2-Aminocyclohexanol hydrochloride (1.096 g), XantPhos (251 mg),tert-butyl 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 11), (2.588 g), palladium (II) acetate (49 mg) toluene(46.2 mL) and TEA (3.02 mL) were placed in a sealed microwave vial witha CO balloon attached. The microwave tube was purged with CO then heatedto 80° C. overnight at which point LC-MS indicated completion. Thereaction was then cooled to rt and filtered through celite, washing withEtOAc. The residue at the bottom of the flask was then sonicated inEtOAc and filtered through the same celite pad. The filtrate was reducedin vacuo. The residue was dissolved in MeOH (5 mL) and loaded onto anSCX-2 cartridge, washing with 5 CV MeOH, then eluting with 5 CV 2MNH3/MeOH. The NH₃-containing fractions were combined and reduced invacuo. The residue was purified by column chromatography (normal phase,25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100%EtOAc in hexane followed by 0% to 100% EtOAc in hexane). To yield thedesired product (2.147 g).

LCMS: m/z 374.62 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.24-1.57 (m, 4H) 1.67 (s, 9H) 1.79 (d,J=10.2 Hz, 2H) 2.14 (d, J=11.4 Hz, 2H) 2.76 (s, 3H) 3.60 (d, J=4.3 Hz,1H) 3.89 (br. S., 1H) 7.13 (d, J=4.8 Hz, 1H) 8.40 (d, J=5.0 Hz, 1H) 8.57(br. s., 1H) 9.43 (d, J=6.2 Hz, 1H)

(9) Intermediate 13:N-((1S,2S)-2-Hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 12), (2.147 g) in 1,4-dioxane (5 mL) stirred undernitrogen at rt was added 4M HCl/Dioxane (10 mL) and the reaction wasstirred at rt for 2 h. The reaction was incomplete by LC-MS, so anadditional 20 mL 4M HCl/Dioxane was added and the reaction was stirredat rt overnight. Incomplete by LC-MS, so a further 20 mL 4M HCl/Dioxanewas added and the reaction was stirred at rt for 8 h, at which pointLC-MS indicated completion. The reaction was then reduced in vacuo,dissolved in MeOH (5 mL) and loaded onto an SCX-2 cartridge, washingwith 5CV MeOH. The product was then eluted with 2M NH3/MeOH, and theNH3-containing fractions were combined and reduced in vacuo to yield thedesired compound (1.493 g) which was taken on as such without furtherpurification.

LCMS: m/z 274.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.24-1.61 (m, 4H) 1.78 (d, J=7.9 Hz, 2H)2.06-2.26 (m, 2H) 2.52 (s, 3H) 3.63 (td, J=9.9, 4.4 Hz, 1H) 3.86-4.01(m, 1H) 6.84 (d, J=4.9 Hz, 1H) 8.03 (br. s., 1H) 8.23 (d, J=4.9 Hz, 1H)9.24 (d, J=6.9 Hz, 1H) 11.00 (br. s., 1H)

Intermediate 17: Synthesis of7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 14: 7-Chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine

To a mixture of 7-chloro-1H-pyrrolo[3,2-b]pyridine (Intermediate 6), (3g) and DMF (46.4 mL) was added KOH (4.19 g) and 12 (5.49 g) and left tostir at rt for 1 h. The reaction mixture was then added to a solution ofsodium bisulfite (2.5 g), water (370 mL) and 28-30% NH₄OH (25 mL) cooledin an ice-bath. A precipitate formed which was collected by filtrationto give the desired compound (4.99 g).

LCMS: m/z 279.32 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 7.36 (d, J=5.0 Hz, 1H) 7.93 (s, 1H) 8.35(d, J=5.0 Hz, 1H) 12.32 (br. s., 1H)

(2) Intermediate 15: tert-Butyl7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate14), (4.99 g) and DMAP (285 mg) in DCM (43.4 mL), was added dropwise asolution of di-tert-butyl dicarbonate (5.87 g) in DCM (10 mL) and thereaction mixture left to stir at rt for 4 h 20 min. The reaction mixturewas evaporated under vacuum and then loaded onto a column in DCM (normalphase, 100 g, Biotage SNAP cartridge KP-Sil, 53 mL/min, gradient 0-5%EtOAc in n-hexane) to give the desired compound (6.04 g).

LCMS: m/z 379.37 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.68 (s, 9H) 7.35 (d, J=5.1 Hz, 1H) 7.99 (s,1H) 8.51 (d, J=5.1 Hz, 1H)

(3) Intermediate 16: tert-Butyl7-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 15), (6.04 g), Pd(OAc)₂ (107 mg),(1S,2S)-2-aminocyclohexanol hydrochloride (3.63 g), XantPhos (554 mg),toluene (144 mL) and TEA (6.67 mL) was added to a two-neckround-bottomed flask fitted with a reflux condenser. This was purgedwith CO and stirred at 80° C. overnight under a CO balloon. The reactionmixture was allowed to cool to rt and then diluted with EtOAc andtransferred to a separatory funnel. The remaining solid in the microwavetube was dissolved in THF by sonication and added to the EtOAc layer.The organic layer was washed with water (2×) and brine. The combinedaqueous layers were extracted with EtOAc and the combined organic layersdried over MgSO₄, filtered and evaporated under vacuum to give a solid(8.48 g) which was taken on crude without further purification.

LCMS: m/z 394.57 [M+H]⁺.

(4) Intermediate 17:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl7-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 16), (1.03 g) in DCM (5.47 mL) was added TFA (10.92 mL)dropwise and left to stir at rt for 1 h. The solvent was evaporatedunder vacuum and then left under high vacuum for 15 min to give an oil.This was dissolved in DCM and purified using column chromatography(normal phase, 55 g, Biotage SNAP cartridge KP-NH, 25 mL/min, gradient0-100% EtOAc in n-hexane, then 0-20% MeOH in EtOAc) to give the desiredcompound (529 mg)

LCMS: m/z 294.53 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.85-2.70 (m, 8H) 3.64 (td, J=10.1, 4.5 Hz,1H) 3.83-4.09 (m, 1H) 4.68 (br. s, 1H) 7.11 (d, J=5.0 Hz, 1H) 8.15 (br.s., 1H) 8.27 (d, J=5.0 Hz, 1H) 8.93 (d, J=7.1 Hz, 1H) 10.15 (br. s., 1H)

Intermediate 18: Synthesis of1-(4-Fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

To an ice-cold solution of 3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 1), (500 mg) in N,N-dimethylacetamide (5 mL) stirred at rtunder nitrogen was added sodium hydride (98 mg) portionwise and thereaction was stirred for 10 min. 1-(Bromomethyl)-4-fluorobenzene (0.26mL) in DMA (5 mL) was added dropwise and the reaction was stirred at rtovernight, at which point LC-MS indicated presence of the desiredproduct. The reaction was diluted with EtOAc, washed with water (2×),brine (2×), dried (MgSO₄), filtered and evaporated under vacuum. Theresidue was purified by column chromatography (normal phase, 25 g,Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 50% EtOAcin n-hexane) to yield the desired product (649 mg).

LCMS: m/z 353.39 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 5.31 (s, 2H) 6.98-7.20 (m, 5H) 7.45 (s, 1H)7.54 (d, J=8.2 Hz, 1H) 8.59 (d, J=4.5 Hz, 1H)

Intermediate 21: Synthesis of tert-Butyl4-(1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylate

(1) Intermediate 19: 4-Fluorobenzyl1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate

To a solution of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (purchasedfrom Ontario Chemicals Inc.), (771 mg) in DMF (100 mL) stirred at rtunder nitrogen was added K₂CO₃ (1314 mg) and the reaction was stirred atrt for 5 min. 1-(Bromomethyl)-4-fluorobenzene (1.13 mL) was then addedin one portion and the reaction was stirred at rt overnight, at whichpoint LC-MS indicated presence of mainly the desired product. Thereaction was then diluted with water (35 mL) and stirred for 10 min andthen filtered. The residue was collected and dried azeotropically toyield the crude product (1.314 g), which was taken on as such withoutfurther purification.

LCMS: m/z 379.54 [M+H]⁺.

(2) Intermediate 20:1-(4-Fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid

To a solution of 4-fluorobenzyl1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (Intermediate19), (1.314 g) in THF (14.42 mL) and water (4.12 mL) was added lithiumhydroxide monohydrate (0.097 mL) and the reaction was heated to refluxand stirred for 4 h and then cooled to rt and stirred overnight, atwhich point LC-MS indicated disappearance of SM and presence of thedesired product. The reaction was then neutralised by dropwise additionof 2M HCl, then dried azeotropically. The residue (939 mg) was taken onas such without further purification.

LCMS: m/z 271.51 [M+H]⁺.

(3) Intermediate 21: tert-Butyl4-(1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylate

To a solution of1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid(Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogenwas added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stirfor 15 minutes and tert-butyl 4-aminopiperidine-1-carboxylate (82 mg)was introduced. The reaction was left to stir overnight at roomtemperature, at which point LC-MS indicated completion. The reactionmixture was transferred to a seperating flask and EtOAc and water wereadded. The phases were separated and the aqueous phase was extractedtwice more with EtOAc. The organic phases were combined, washed withbrine and the solvent was removed in vacuo. The residue was purified bycolumn chromatography (normal phase, 25 g, Biotage SNAP cartridgeKP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by0-15% MeOH/EtOAc) to give an impure product (184 mg), which was taken onas such without further purification.

LCMS: m/z 453.66 [M+H]⁺.

Intermediate 27: Synthesis of7-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 22:1-(Phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-7-carbonitrile

A mixture of 7-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 7), (1.0 g), Pd(PPh₃)₄ (0.50 g), zinc cyanide (0.50 g) andDMF (10 mL) was purged with nitrogen then microwaved at 130° C. for 0.5h. The reaction mixture was then diluted with EtOAc, washed with waterthe insoluble solid filtered and the layers separate. The organic phasewas washed with more water (2×), brine, dried (MgSO₄), filtered andevaporate under vacuum and the residue was purified by columnchromatography (normal phase, gradient 0% to 50% EtOAc in n-hexane)followed by prep. LCMS to give the pure desired compound (0.88 g).

LCMS: m/z 284.43 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 7.01 (d, J=3.8 Hz, 1H) 7.45-7.67 (m, 4H)8.04 (d, J=7.7 Hz, 2H) 8.14 (d, J=3.8 Hz, 1H) 8.55-8.66 (m, 1H).

(2) Intermediate 23: 1H-pyrrolo[3,2-b]pyridine-7-carbonitrile

A mixture of 1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-7-carbonitrile(Intermediate 22), (6.00 g), EtOH (400 mL) and 10% aq. NaOH (9 mL) washeated at 80° C. for 0.5 h. The reaction mixture was cooled, evaporatedto dryness and and the solid dissolved in EtOAc, washed with brine (2×)and the brine extracts washed with EtOAc (3×), the combined organicphases dried (MgSO₄), filter and evaporate under vacuum. The resultingsolid was suspended in DCM, filtered and washed with more DCM to givethe desired compound (2.02 g). The DCM washes were evaporated and theresidue was purified by column chromatography (normal phase, 50 gsilica, gradient 0% to 50% EtOAc in n-hexane) to give more of thedesired compound (197 mg).

LCMS: m/z 144.40 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 6.77 (d, J=1.7 Hz, 1H) 7.57 (d, J=4.8 Hz,1H) 7.86 (t, J=2.8 Hz, 1H) 8.50 (d, J=4.8 Hz, 1H) 12.36 (br. s., 1H).

(3) Intermediate 24: 3-Iodo-1H-pyrrolo[3,2-b]pyridine-7-carbonitrile

To a mixture of 1H-pyrrolo[3,2-b]pyridine-7-carbonitrile (Intermediate23), (2.20 g) and DMF (36.3 mL) was added KOH (3.28 g) followed byiodine (4.29 g) then the reaction mixture stirred at rt for 1 h 15 min.It was then diluted with EtOAc (300 mL), washed with water (3×80 mL)then brine (2×80 mL). To the combined aqueous phase was added EtOAcwhich caused a precipitate to form which was filtered, washed with waterthen EtOAc to give the desired compound (1.42 g). The combined aqueousphases were extracted with EtOAc (3×) then the combined organic extractsdried (MgSO₄), filtered and evaporated under vacuum to give more of thedesired compound (2.49 g).

LCMS: m/z 270.37 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 7.68 (d, J=4.9 Hz, 1H) 8.07 (s, 1H) 8.56(d, J=4.8 Hz, 1H) 12.83 (br. s., 1H)

(4) Intermediate 25: tert-Butyl7-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 3-iodo-1H-pyrrolo[3,2-b]pyridine-7-carbonitrile(Intermediate 24), (3.91 g) and N,N-dimethylpyridin-4-amine (0.23 g) inDCM (35 mL), was added dropwise a solution of di-tert-butyl dicarbonate(4.76 g) in DCM (35 mL) over 2 min, and the reaction mixture left tostir at r.t. for 1 h. The solvent was evaporated and the residue waspurified by column chromatography (normal phase, 100 g silica, gradient0% to 40% EtOAc in n-hexane) to give the desired compound (4.92 g).

LCMS: m/z 370.39 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.73 (s, 9H) 7.63 (d, J=4.9 Hz, 1H) 8.08 (s,1H) 8.74 (d, J=4.9 Hz, 1H).

(5) Intermediate 26: tert-Butyl7-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 7-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 25), (4.92 g), palladium (II) acetate (90 mg),(1S,2S)-2-aminocyclohexanol hydrochloride (3.03 g), XantPhos (0.46 g)toluene (121 mL) and TEA (5.57 mL) were added to a one necked roundbottom flask. This was purged with CO and stirred at 80° C. for 5 hrunder CO. The reaction mixture was diluted with EtOAc and transferred toa separatory funnel. Remaining solid in the microwave tube was dissolvedin THF by sonication and added to the separatory funnel. The combinedorganic layers were washed with water (2×) then brine. The combinedaqueous layers were extracted with EtOAc (2×) and the combined organicextracts dried over MgSO₄, filtered and evaporated in vacuo to the crudedesired compound which was taken on as such without furtherpurification.

LCMS: m/z 385.65 [M+H]⁺, m/z 285.56 [M+H-Boc]⁺.

(6) Intermediate 27:7-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of tert-butyl7-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 26), (5.12 g), DCM (57.3 mL) and TFA (28.6 mL) werestirred for 1 h. The solvent was evaporated and the residue purified bycolumn chromatography (normal phase, 110 g amino silica, gradient 0% to100% EtOAc in n-hexane then gradient 0% to 20% MeOH in EtOAc) followedby another purification by column chromatography (normal phase, 110 gamino silica, gradient 0% to 100% EtOAc in n-hexane then gradient 0% to20% MeOH in EtOAc) to give the pure desired compound (2.66 g). The mixedfractions were evaporated and purified again by column chromatography(normal phase, 55 g amino silica, gradient 0% to 100% EtOAc in n-hexanethen gradient 0% to 20% MeOH in EtOAc) to give more of the pure desiredcompound (649 mg).

LCMS: m/z 285.52 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 1.15-1.37 (m, 4H) 1.57-1.72 (m, 2H)1.84-1.92 (m, 1H) 1.98-2.08 (m, 1H) 3.37-3.45 (m, 1H) 3.67-3.76 (m, 1H)7.75 (d, J=4.9 Hz, 1H) 8.32 (d, J=2.7 Hz, 1H) 8.52-8.60 (m, 1H) 8.66 (d,J=4.8 Hz, 1H) 13.04 (br. s., 1H).

Intermediate 33: Synthesis of trans-2-Amino-5,5-difluorocyclohexanol

(1) Intermediate 28: 4,4-Difluorocyclohexanol

To a stirred solution of lithium aluminium hydride (46.6 mL, 4M indiethyl ether) at 0° C. was added a solution of4,4-difluorocyclohexanone (Purchased from Manchester Organics), (25 g)in diethyl ether (250 mL) dropwise. After addition, the reaction mixturewas allowed to warm to rt and stirred for 30 minutes. To the reactionmixture was added water (7 mL) dropwise, followed by 15% aqueous sodiumhydroxide (7 mL), followed by water (21 mL). The resulting solid wasfiltered off and washed with diethyl ether. The filtrate was dried(MgSO₄), filtered and evaporated to afford the title compound (28.38 g).

¹H NMR (600 MHz, CDCl₃) ppm 1.69-1.78 (m, 2H) 1.80-1.93 (m, 4H)2.08-2.17 (m, 2H) 3.73 (q, J=7.0 Hz, 1H) 3.93 (m, 1H)

(2) Intermediate 29: 4,4-Difluorocyclohexyl methanesulfonate

To a solution of 4,4-difluorocyclohexanol (Intermediate 28), (28.38 g)in anhydrous DCM (200 mL) and TEA (34.6 mL) under nitrogen at 0° C. wasadded methanesulfonyl chloride (17.87 ml) dropwise and the resultingmixture was allowed to warm to rt. After 1.5 hours, TEA (14.51 ml) wasadded and stirring continued for 1 hour. Further TEA (14.51 mL) andmethanesulfonyl chloride (8.12 mL) was added and stirring continued for30 minutes. The mixture was quenched with an aqueous solution ofsaturated ammonium chloride and stirred for 5 minutes and the layersseparated. The organic layer was washed with aqueous ammonium chloridesolution, dried (MgSO₄), filtered and evaporated. The residue waspurified by column chromatography (normal phase, Biotage SNAP cartridgeKP-Sil, gradient 0% to 60% diethyl ether in pentane) to afford the titlecompound (46.21 g).

¹H NMR (400 MHz, CDCl₃) ppm 1.87-2.22 (m, 8H) 3.05 (s, 3H) 4.92 (d,J=2.3 Hz, 1H)

(3) Intermediate 30: 4,4-Difluorocyclohex-1-ene

DBU (39.0 mL) was added to 4,4-difluorocyclohexyl methanesulfonate(Intermediate 29), (36.95 g) and the mixture heated to 100° C. for 1.5hours with stirring. The title compound was isolated by distillation(11.28 g), boiling point 96° C. at 760 mmHg.

¹H NMR (400 MHz, CDCl₃) ppm 2.01 (tt, J=13.9, 6.7 Hz, 2H) 2.21-2.39 (m,2H) 2.52 (t, J=14.5 Hz, 2H) 5.48-5.65 (m, 1H) 5.67-5.82 (m, 1H)

(4) Intermediate 31: 3,3-Difluoro-7-oxabicyclo[4.1.0]heptane

To a solution of 4,4-difluorocyclohex-1-ene (Intermediate 30), (11.25 g)in DCM (120 mL) at 0° C., was added mCPBA (42.7 g) portionwise. Afteraddition, the reaction mixture was allowed to warm to rt and stirredovernight. An aqueous saturated solution of sodium sulphite was addedand the resulting solid was collected by filtration. The filtrate waspartitioned between DCM and water, and the aqueous layer re-extractedwith DCM. The combined organic layer was washed with aqueous saturatedsodium bicarbonate (2×), dried (MgSO₄), filtered and evaporated toafford the title compound (16.87 g).

¹H NMR (600 MHz, CDCl₃) ppm 1.79-1.92 (m, 2H) 2.03-2.12 (m, 1H)2.22-2.46 (m, 3H) 3.18-3.22 (m, 1H) 3.24 (m, 1H)

(5) Intermediate 32: trans-2-Azido-5,5-difluorocyclohexanol

To a suspension of(R,R)—N,N-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminochromium(III)chloride (1.204 g) in diethyl ether (30 mL) was added3,3-difluoro-7-oxabicyclo[4.1.0]heptane (Intermediate 31), (12.77 g) andthe reaction mixture stirred for 15 minutes. Trimethylsilyl azide (13.27mL) was added to the reaction mixture and the resulting solution wasstirred at rt overnight. The mixture was evaporated and the residueapplied onto a normal phase, Biotage SNAP KP-Sil cartridge. Elution with40% ether in hexane gave an oil which was dissolved in methanol (30 mL)and treated with (+/−)-10-Camphorsulfonic acid (1.106 g). The mixturewas stirred at rt for 30 minutes and then evaporated. The residue waspurified by column chromatography (normal phase, Biotage SNAP cartridgeKP-Sil, gradient 0% to 30% diethyl ether in n-hexane) to afford thetitle compound (4.40 g).

¹H NMR (600 MHz, CDCl₃) ppm 1.61-1.71 (m, 1H) 1.76-1.93 (m, 2H) 2.08 (m,1H) 2.13-2.23 (m, 1H) 2.32 (br. s., 1H) 2.42-2.53 (m, 1H) 3.30-3.41 (m,1H) 3.69-3.74 (m, 1H)

(6) Intermediate 33: trans-2-Amino-5,5-difluorocyclohexanol

To a solution of trans-2-azido-5,5-difluorocyclohexanol (Intermediate32), (4.35 g) in methanol (50 mL), was added 10% wet palladium on carbon(500 mg) and stirred under an atmosphere of hydrogen overnight. Theresidue was filtered through a pad of celite, washed with methanol andevaporated. The residue was dissolved in methanol and filtered throughanother pad of celite, a PTFE filter, then evaporated and purified bySCX-2 cartridge to afford the title compound (3.37 g).

¹H NMR (600 MHz, CDCl₃) ppm 1.36-1.50 (m, 1H) 1.67-2.17 (m, 7H)2.41-2.60 (m, 2H) 3.36-3.46 (m, 1H)

Intermediate 37: Synthesis of cis-2-Amino-5,5-difluorocyclohexanol

(1) Intermediate 34: 5,5-Difluoro-2,2-dimethoxycyclohexanol

To a solution of 4,4-difluorocyclohexanone (purchased from ManchesterOrganics), (7.0 g) in methanol (70 mL) was added potassium hydroxide(7.03 g). The mixture was cooled to 0° C. then a solution of iodine(14.6 g) in methanol (140 mL) was added over 60 minutes. The reactionmixture was returned to room temperature and stirred for a further 18hours. It was then concentrated under vacuum, re-suspended in DCM (100mL) and passed through a filter. Activated carbon (3 g) was added to thefiltrate. The resulting suspension was stirred at room temperature for60 minutes then filtered through a pad of celite. The filtrate wasconcentrated under vacuum to approximately 10 ml then purified by columnchromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50mL per min, gradient 0% to 10% methanol in DCM) to give the desiredcompound (5.28 g).

¹H NMR (400 MHz, CDCl₃) ppm 1.78-2.27 (m, 6H) 3.29 (s, 3H) 3.31 (s, 3H)3.99 (br. s, 1H).

(2) Intermediate 35: 2-(Benzyloxy)-4,4-difluorocyclohexanone

To a solution of 5,5-difluoro-2,2-dimethoxycyclohexanol (Intermediate34), (1.6 g) in DMF (30 mL) at 0° C. under an atmosphere of nitrogen wasadded sodium hydride (391 mg, 60 wt %) in a portionwise manner. Themixture was stirred at 0° C. for 30 minutes. Benzyl bromide (1.67 g) wasadded, the reaction mixture allowed to return to room temperature andstirring continued for 19 hours. The reaction mixture was diluted withwater and extracted into EtOAc (2×). The combined organic extracts werewashed with water (3×) then brine (1×), dried (Na₂SO₄), filtered andevaporated under vacuum. The residue was purified by columnchromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50mL per min, gradient 0% to 20% EtOAc in hexane) to give the desiredcompound (2.65 g).

¹H NMR (400 MHz, CDCl₃) ppm 2.25 (m, 2H) 2.43 (m, 1H) 2.58 (m, 2H) 2.75(m 1H) 4.15 (dd, J=11.7, 6.6 Hz, 1H) 4.52 (d, J=11.7 Hz, 1H) 4.86 (d,J=11.7 Hz, 1H) 7.33 (m, 1H) 7.38 (m, 4H).

(3) Intermediate 36:cic-2-(Benzyloxy)-4,4-difluoro-N—((S)-1-phenylethyl)cyclohexanamine

To a solution of 2-(benzyloxy)-4,4-difluorocyclohexanone (Intermediate35), (2.0 g) in 1,2-dichloroethane (75 mL) under an atmosphere ofnitrogen was added (S)-1-phenylethanamine (1.11 g) followed by aceticacid (0.48 mL) and sodium triacetoxyborohydride (2.65 g). The reactionmixture was stirred at room temperature for two hours. It was thenquenched with saturated sodium bicarbonate solution, diluted with waterand extracted into EtOAc (2×). The combined organic extracts were washedwith water (3×) then brine (1×), dried (Na₂SO₄), filtered and evaporatedunder vacuum. The residue was purified by column chromatography (normalphase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 0%to 20% EtOAc in hexane) to isolate the desired compound, a singleenantiomer of cis relative stereochemistry but unknown absoluteconfiguration, (1.68 g).

LCMS: m/z 346.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.33 (d, J=6.3 Hz, 3H) 1.38 (br. s, 1H),1.57 (m, 2H), 1.68 (br. s, 1H), 2.03 (m, 2H) 2.36 (m, 1H) 2.98 (br. s,1H), 3.69 (q, J=6.6 Hz, 1H) 3.73 (m, 1H) 4.54 (d, J=11.8 Hz, 1H) 4.65(d, J=11.8 Hz, 1H) 7.34 (m, 10H).

(4) Intermediate 37: cis-2-Amino-5,5-difluorocyclohexanol

To a solution ofcis-2-(benzyloxy)-4,4-difluoro-N—((S)-1-phenylethyl)cyclohexanamine(Intermediate 36), (1.68 g) in methanol (50 mL) was added Pearlman'scatalyst (342 mg, 20 wt %, 50% H₂O). The mixture was purged sequentiallywith nitrogen and vacuum then stirred under an atmosphere of hydrogen atroom temperature. Additional catalyst was added after 6 hours (172 mg)and 18 hours (342 mg) with appropriate purges of nitrogen and vacuumbefore re-introduction of the hydrogen atmosphere. After 24 hours thereaction mixture was passed through a pad of celite and evaporated undervacuum. The residue was redissolved in methanol. Pearlman's catalyst(342 mg) was added and the mixture purged with nitrogen and vacuumbefore re-applying the hydrogen atmosphere. After 20 hours the reactionmixture was passed through a pad of celite and evaporated under vacuum.The residue was washed with DCM then dried in air to give the desiredcompound, a single enantiomer of cis relative stereochemistry butunknown absolute configuration, (383 mg).

¹H NMR (400 MHz, DMSO-d₆) ppm 1.75 (m, 1H) 1.92 (m, 2H) 2.11 (m, 3H)4.01 (br. s, 1H) 5.71 (d, J=3.7 Hz, 1H) 7.99 (br. s, 3H).

Intermediate 45: Synthesis ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 38: 2-Bromo-4-methoxypyridin-3-amine

To a solution of 4-methoxypyridin-3-amine (purchased from Ark PharmInc.), (3 g) in concentrated HCl (22.17 mL) was added bromine (1.49 mL)dropwise over a 30 s period and the mixture stirred at rt for 1 h andthen at 55° C. over the weekend. The reaction mixture was allowed tocool to rt and then poured into ice (250 g). Concentrated NH₄OH wasadded until the pH of the solution was basic (pH ˜9). The resultingsolution was then partitioned between H₂O and EtOAc and the two layersseparated. The aqueous layer was extracted with EtOAc (2×) and thecombined organic layers washed with water and brine, dried (MgSO₄),filtered and evaporated under vacuum to give a solid which was dissolvedin DCM and purified by column chromatography (normal phase, 100 g,Biotage SNAP cartridge KP-Sil, 50 mL/min, gradient 0-20% EtOAc inn-hexane) to give the desired product (2.74 g).

LCMS: m/z 203.37 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 3.93 (s, 3H) 3.95-4.60 (br. s., 2H) 6.69 (d,J=5.4 Hz, 1H) 7.76 (d, J=5.3 Hz, 1H)

(2) Intermediate 39: Ethyl (2-bromo-4-methoxypyridin-3-yl)carbamate

To an ice-cold solution of 2-bromo-4-methoxypyridin-3-amine(Intermediate 38), (2.74 g) in pyridine (102 mL) was added ethylchloroformate (1.91 mL) dropwise and then stirred at rt for 45 min. Thereaction mixture was cooled in an ice-bath and more ethyl chloroformate(9 mL) added and the mixture left to stir overnight at rt. The reactionmixture was diluted with EtOAc and washed with sat. aq. NaHCO₃. Theaqueous layer was extracted with EtOAc and the combined organic layerswashed with brine, dried over MgSO₄, filtered and evaporated undervacuum to give a solid. Product was observed in the aqueous layer byLC-MS, so this was re-extracted with EtOAc (3×) and evaporated undervacuum to give a solid which was combined with the previous solid,dissolved in DCM and purified by column chromatography (normal phase, 50g, Biotage SNAP cartridge KP-Sil, 50 mL/min, gradient 10-70% EtOAc inn-hexane) to give the desired product (2.35 g).

LCMS: m/z 275.43 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.32 (t, J=7.1 Hz, 3H) 3.93 (s, 3H) 4.24 (q,J=7.1 Hz, 2H) 6.06 (br. s., 1H) 6.86 (d, J=5.6 Hz, 1H) 8.19 (d, J=5.6Hz, 1H)

(3) Intermediate 40: Ethyl(4-methoxy-2-((trimethylsilyl)ethynyl)pyridin-3-yl)carbamate

To a round bottomed flask equipped with a condenser, was added ethyl(2-bromo-4-methoxypyridin-3-yl)carbamate (Intermediate 39), (2.6 g), TEA(2.60 mL), bis(triphenylphosphine)palladium (II) chloride (332 mg), CuI(144 mg) and TMS-acetylene (1.84 g) in dry THF (48.2 mL) and heated at60° C. under N₂ over the weekend. The mixture was evaporated undervacuum to give a solid which was dissolved in DCM and purified by columnchromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50mL/min, gradient 0-40% EtOAc in n-hexane) to give the desired product(2.16 g).

LCMS: m/z 293.55 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.28 (s, 9H) 1.32 (t, J=7.0 Hz, 3H) 3.92 (s,3H) 4.24 (q, J=7.1 Hz, 2H) 6.18 (br. s., 1H) 6.84 (d, J=5.5 Hz, 1H) 8.34(d, J=5.5 Hz, 1H)

(4) Intermediate 41: 7-Methoxy-1H-pyrrolo[3,2-b]pyridine

TBAF (8.25 mL) (1 M in THF) was added to a solution of ethyl(4-methoxy-2-((trimethylsilyl)ethynyl)pyridin-3-yl)carbamate(Intermediate 40), (2.01 g) in THF (9.63 mL) and refluxed at 70° C.under N₂ for 4 h 45 min. The reaction mixture was allowed to cool to rtand then diluted with EtOAc (200 mL) and washed with water (40 mL) andbrine (40 mL). The aqueous layers were extracted with EtOAc (2×40 mL)and the combined organic layers dried over MgSO₄, filtered andevaporated under vacuum to give an oil which was dissolved in EtOAc andpurified by column chromatography (normal phase, 50 g, Biotage SNAPcartridge KP-Sil, 50 mL/min, 80% EtOAc in hexane, then 0-5% MeOH inEtOAc) to give the desired product (579 mg).

LCMS: m/z 149.45 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) ppm 4.05 (s, 3H) 6.55 (br. s., 1H) 6.77 (br. s.,1H) 7.43 (d, J=2.5 Hz, 1H) 7.89-8.61 (m, 1H)

(5) Intermediate 42: 3-Iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine

To a mixture of 7-methoxy-1H-pyrrolo[3,2-b]pyridine (Intermediate 41),(102 mg) and DMF (3 mL) was added KOH (147 mg) and 12 (192 mg) and leftto stir at rt for 90 min. The crude product was diluted with MeOH andpurified using an SCX-2 cartridge (washed sequentially with MeOH, H₂O,MeOH and product eluted using 2 M methanolic ammonia). The solution wasevaporated under vacuum to give the desired product (178 mg).

LCMS: m/z 275.37 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) ppm 4.07 (s, 3H) 6.85 (d, J=5.6 Hz, 1H) 7.53 (s,1H) 8.27 (d, J=5.5 Hz, 1H)

(6) Intermediate 43: tert-Butyl3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a suspension of 3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine(Intermediate 42), (1.01 g) and DMAP (58.7 mg) in DCM (8.9 mL), wasadded dropwise a solution of di-tert-butyl dicarbonate (1.21 g) in DCM(2 mL) over 30 s, and the reaction mixture left to stir at rt overnight.The reaction mixture was evaporated under vacuum and then loaded onto acolumn in DCM (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25mL/min, gradient 0-30% EtOAc in n-hexane) to give the desired product(1.18 g).

LCMS: m/z 375.44 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.65 (s, 9H) 4.02 (s, 3H) 6.82 (d, J=5.5 Hz,1H) 7.93 (s, 1H) 8.51 (d, J=5.6 Hz, 1H)

(7) Intermediate 44: tert-Butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 3-iodo-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 43), (924 mg), Pd(OAc)₂ (33 mg),(1S,2S)-2-aminocyclohexanol hydrochloride (562 mg), XantPhos (169 mg),toluene (22 mL) and TEA (1.03 mL) were added to a round bottomed flask.This was purged with CO and stirred at 80° C. overnight under CO. Thereaction mixture was diluted with EtOAc (250 mL) and washed with water(2×70 mL) and brine (70 mL). The combined aqueous layers were extractedwith EtOAc (70 mL) and the combined organic layers dried over MgSO₄,filtered and evaporated under vacuum to give a solid (1.22 g) which wastaken on as such without further purification.

LCMS: m/z 390.65 [M+H]⁺.

(8) Intermediate 45:N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 44), (312 mg) in DCM (2 mL) was added TFA (3.3 mL)dropwise and left to stir at rt for 1 h 15 min. The solvent wasevaporated under vacuum to give an oil which was dissolved in DCM andpurified using column chromatography (normal phase, 28 g, Biotage SNAPcartridge KP-NH, 25 mL/min, gradient 0-5% MeOH in EtOAc) to give thedesired product (157 mg).

LCMS: m/z 290.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.05-2.23 (m, 8H) 3.58 (td, J=9.9, 4.5 Hz,1H) 3.82-3.97 (m, 1H) 4.02 (s, 3H) 6.63 (d, J=5.5 Hz, 1H) 8.01 (s, 1H)8.32 (d, J=5.5 Hz, 1H) 9.11 (d, J=6.6 Hz, 1H)

Intermediate 49: Synthesis ofN-((1S,2S)-2-hydroxycyclohexyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 46: 3-Iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine

To a mixture of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (Purchased fromCombi blocks Inc.), (500 mg) and DMF (8 mL) was added KOH (719 mg)followed by iodine (942 mg) then the mixture stirred for 2 h. It wasdiluted with EtOAc, washed with water (3×), brine (2×), dried (MgSO₄),filtered and evaporated under vacuum to give the crude product (925 mg),which was used in the next step without further purification.

LCMS: m/z 275.66 [M+H]⁺.

(2) Intermediate 47: tert-Butyl3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (Intermediate46), (925 mg), 4-dimethylaminopyridine (54 mg) and DCM (7.2 mL) wasadded dropwise a solution of di-t-butyldicarbonate (1.1 g) in DCM (4 mL)and the reaction mixture stirred for 1 h 15 min. The solvent was thenevaporated and the residue was purified by column chromatography (normalphase, 28 g amino silica, 50 g silica, Biotage SNAP cartridge KP-Sil,gradient 0% to 10% EtOAc in n-hexane) to give the desired compound (970mg).

LCMS: m/z 375.41[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.65-1.71 (m, 9H) 4.07 (s, 3H) 6.74 (d,J=8.93 Hz, 1H) 7.86 (s, 1H) 8.18-8.31 (m, 1H).

(3) Intermediate 48: tert-Butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 47), (950 mg), (1S,2S)-2-aminocyclohexanol hydrochloride(577 mg), palladium (II) acetate (17.10 mg), XantPhos (88 mg), toluene(23 mL) and TEA (1.2 mL) were placed in a 25 mL microwave tube with aballoon of CO. The reaction mixture was purged with CO then heated to80° C. for 2 h 15 min (CO was bubbled through reaction mixture when itfirst reached 80° C.). The reaction mixture was cooled, poured ontoEtOAc and the remaining solid in the reaction flask was added to theEtOAc organic phases by dissolving in water and the organic phaseswashed with water (2×) then brine. The combined organic extracts weredried (MgSO₄), filter and evaporate under vacuum to give the crudedesired compound (989 mg), which was used crude.

LCMS: m/z 390.64 [M+H]⁺.

(4) Intermediate 49:N-((1S,2S)-2-hydroxycyclohexyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of tert-butyl3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 48), (989 mg), DCM (11 mL) and TFA (5.6 mL) was stirredfor 1 h. The solvent was evaporated and the residue purified by columnchromatography (normal phase, 55 g amino silica, Biotage SNAP cartridgeKP-Sil, gradient 0% to 100% EtOAc in n-hexane followed by gradient0%-15% EtOAc in MeOH) to give the desired compound (500 mg).

LCMS: m/z 299.55 [M+H]⁺.

1H NMR (400 MHz, DMSO-d₆) ppm 1.08-1.40 (m, 4H) 1.56-1.71 (m, 2H) 1.90(d, J=10.0 Hz, 1H) 2.13 (d, J=12.4 Hz, 1H) 3.40 (br. s., 1H) 3.61-3.72(m, 1H) 3.94 (s, 3H) 4.84 (d, J=4.0 Hz, 1H) 6.68 (d, J=8.8 Hz, 1H) 7.83(d, J=8.8 Hz, 1H) 7.96 (s, 1H) 8.67 (d, J=6.9 Hz, 1H).

Intermediate 53: Synthesis of5-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 50: 5-Chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine

To a mixture of 5-chloro-1H-pyrrolo[3,2-b]pyridine (Purchased from ArkPharm Inc.), (500 mg) and DMF (7.7 mL) was added KOH (699 mg) followedby iodine (915 mg) then the reaction mixture stirred for 1 h. It wasthen diluted with EtOAc, washed with water (3×), brine (2×), dried(MgSO₄), filtered and evaporated under vacuum to give the crude desiredcompound (1.1 g), which was used in the next step without furtherpurification.

LCMS: m/z 279.37[M+H]⁺.

(2) Intermediate 51: tert-Butyl5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a mixture of 5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate50), (910 mg), 4-dimethylaminopyridine (52 mg) and DCM (7.0 mL) wasadded dropwise a solution of di-t-butyldicarbonate (1.07 g) in DCM (2mL) and the reaction mixture stirred for two days. The solvent wasevaporated and the residue purified by column chromatography (normalphase, 50 g silica, Biotage SNAP cartridge KP-Sil, gradient 0% to 10%EtOAc in n-hexane) to give the desired compound (1.18 g).

LCMS: m/z 379.35[M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.69 (s, 9H) 7.31 (d, J=8.6 Hz, 1H) 7.98 (s,1H) 8.28-8.39 (m, 1H).

(3) Intermediate 52: tert-Butyl5-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 5-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 51), (600 mg), (1S,2S)-2-aminocyclohexanol hydrochloride(360 mg), palladium (II) acetate (10.7 mg), XantPhos (55 mg), toluene(14.4 mL) and TEA (0.72 mL) were placed in a 25 mL microwave tube with aballoon of CO. The reaction mixture was purged with CO then heated to80° C. for 2 h (CO was bubbled through reaction mixture when it firstreached 80° C.). The reaction mixture was cooled and poured onto EtOAcand the remaining solid in the reaction flask was added to the EtOAcorganic phases by dissolving in water and the organic phases washed withwater (2×) then brine and the combined organic extracts dried (MgSO₄),filtered and evaporated under vacuum. The crude desired compound wastaken on as such.

LCMS: m/z 394.58 [M+H]⁺.

(4) Intermediate 53:5-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl5-chloro-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 52), (624 mg) in DCM (7 mL) was added TFA (3.5 mL) and thereaction mixture stirred for 2 h. The solvent was evaporated and theresidue purified by column chromatography (normal phase, 28 g aminosilica, Biotage SNAP cartridge KP-Sil, gradient 0% to 100% EtOAc inn-hexane then gradient 0% to 20% MeOH in EtOAc) to give the desiredcompound (292 mg).

LCMS: m/z 294.52[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.06-1.43 (m, 4H) 1.64 (d, J=5.4 Hz, 2H)1.79-1.92 (m, 1H) 1.99-2.09 (m, 1H) 3.42 (br. s., 1H) 3.67-3.80 (m, 1H)4.80 (br. s., 1H) 7.29 (d, J=8.6 Hz, 1H) 7.97 (d, J=8.4 Hz, 1H) 8.21 (s,1H) 8.28 (d, J=7.6 Hz, 1H).

Intermediate 58: Synthesis of1-(4-(1H-Pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine

(1) Intermediate 54:5-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine

A mixture of 5-bromo-1H-pyrrolo[3,2-b]pyridine (Purchased from BepharmLtd.), (1.00 g), DCM (30.0 mL), benzenesulfonyl chloride (0.97 mL),tetrabutylammonium hydrogen sulfate (220 mg) and 50% aq. sodiumhydroxide (0.96 mL) was stirred for 1 h to give a suspension. Saturatedaq. NaHCO₃ was added, the layers separated and the aqueous phase wasextracted with more DCM (2×), the combined organic extracts were dried(MgSO₄), filtered and evaporated under vacuum. Adding methanol (˜30 mL)caused the product to precipitate. The suspension was cooled in anice-bath and the ice-cold suspension was filtered and the solid washedwith ice-cold methanol to give the desired compound (1.12 g). The motherliquor was evaporated and the residue purified by column chromatography(normal phase, 28 g amino silica, Biotage SNAP cartridge KP-Sil,gradient 0% to 100% EtOAc in n-hexane) to give more of the desiredcompound (600 mg).

LCMS: m/z 339.37 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 6.84 (dd, J=3.7, 0.7 Hz, 1H) 7.41 (d, J=8.7Hz, 1H) 7.47-7.54 (m, 2H) 7.59-7.65 (m, 1H) 7.80 (d, J=3.8 Hz, 1H)7.85-7.91 (m, 2H) 8.15 (dd, J=8.7, 0.7 Hz, 1H).

(2) Intermediate 55:5-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine

A mixture of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 54), (1.71 g) and Pd(PPh₃)₄ (586 mg) was de-aerated byplacing under high vacuum then purging with nitrogen (3×). To thesesolids was added THF (36 mL) then a 2M THF solution of methylzincchloride (5.07 mL) and the reaction mixture heated to 90° C. for 1 h. Itwas then cooled, quenched with sat. aq. NH₄C₁, extracted with EtOAc(3×), the combined organic extracts dried (MgSO₄), filtered andevaporated under vacuum. The residue was purified by columnchromatography (normal phase, 50 g silica, Biotage SNAP cartridgeKP-Sil, gradient 0% to 80% EtOAc in n-hexane) to give the impure desiredcompound (1.60 g) which was taken on as such.

LCMS: m/z 274.46 [M+H]⁺.

(3) Intermediate 56: 5-Methyl-1H-pyrrolo[3,2-b]pyridine

A mixture of 5-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(Intermediate 55), (1.38 g), ethanol (96 mL) and 10% aq. sodiumhydroxide (47 mL) was heated at 90° C. for 1 h. It was then cooled,poured onto brine, extracted with EtOAc (3×), the combined organicextracts dried (MgSO₄) and the combined organic phases filtered andevaporated under vacuum. The residue was purified by columnchromatography (normal phase, 25 g silica, Biotage SNAP cartridgeKP-Sil, gradient 0% to 100% EtOAc in n-hexane) to give the impuredesired compound (356 mg) which was taken on as such.

LCMS: m/z 133.41 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 2.63 (s, 3H) 6.61 (dd, J=3.2, 0.9 Hz, 1H)6.97 (d, J=8.3 Hz, 1H) 7.39 (d, J=3.3 Hz, 1H) 7.62 (dd, J=8.3, 0.6 Hz,1H)

(4) Intermediate 57:1-(4-(1H-Pyrazol-1-yl)benzyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine

To an ice-cold suspension of 5-methyl-1H-pyrrolo[3,2-b]pyridine(Intermediate 56), (350 mg) in N,N-dimethylacetamide (6.5 mL) was addedsodium hydride (127 mg) in one portion then the reaction mixture stirredfor 20 min. 1-(4-(Bromomethyl)phenyl)-1H-pyrazole (Purchased from ButtPark Ltd.), (691 mg) in DMA (0.8 mL) was added dropwise followed bystirring at rt for 30 min. The reaction mixture was diluted with EtOAc,washed with water (2×), brine, dried (MgSO₄), filtered and evaporatedunder vacuum then left under high vacuum. The residue was purified bycolumn chromatography (normal phase, 25 g silica, Biotage SNAP cartridgeKP-Sil, gradient 0% to 100% EtOAc in n-hexane) to give the desiredcompound (734 mg).

LCMS: m/z 289.53 [M+H]⁺.

¹H NMR (600 MHz, CDCl₃) ppm 2.72 (s, 3H) 5.37 (s, 2H) 6.48 (t, J=2.0 Hz,1H) 6.78 (br. s., 1H) 7.00 (d, J=8.5 Hz, 1H) 7.20 (d, J=8.5 Hz, 2H) 7.39(d, J=2.6 Hz, 1H) 7.50 (d, J=8.2 Hz, 1H) 7.67 (d, J=8.5 Hz, 2H) 7.73 (d,J=1.5 Hz, 1H) 7.90 (d, J=2.6 Hz, 1H).

(5) Intermediate 58:1-(4-(1H-Pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine

A mixture of1-(4-(1H-pyrazol-1-yl)benzyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine(Intermediate 57), (200 mg), DCM (9 mL) and pyridine (0.084 mL) wascooled to −78° C. and a solution of bromine (0.036 mL) in DCM (4 mL) wasadded dropwise. After 20 min the reaction mixture was poured onto amixture of sat. aq. NaHCO₃ (9 mL) and Na₂S₂O₃ (9 mL) and stirred for 1h. The layers were separated, the aqueous phase extracted with DCM (2×),the combined organic extracts dried (MgSO₄), filtered and evaporatedunder vacuum. The residue was purified by column chromatography (normalphase, 25 g silica, Biotage SNAP cartridge KP-Sil, gradient 0% to 50%EtOAc in n-hexane) to give the desired compound (203 mg).

LCMS: m/z 367.46, 369.45 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 2.75 (s, 3H) 5.33 (s, 2H) 6.46-6.50 (m, 1H)7.04 (d, J=8.4 Hz, 1H) 7.21 (d, J=8.7 Hz, 2H) 7.40 (s, 1H) 7.50 (d,J=8.4 Hz, 1H) 7.65-7.70 (m, 2H) 7.73 (d, J=1.6 Hz, 1H) 7.90 (d, J=2.3Hz, 1H).

Intermediate 63: Synthesis of5-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 59: 1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

A mixture of 5-bromo-1H-pyrrolo[3,2-b]pyridine (500 mg), Pd(PPh₃)₄ (176mg), zinc cyanide (179 mg) and DMF (5.1 mL) were stirred at 80° C.overnight. More zinc cyanide (90 mg) and Pd(PPh₃)₄ (90 mg) were addedand the stirring continued at 80° C. for 5 h. The reaction mixture wascooled, diluted with EtOAc, water was added and the insolubleprecipitate filtered, washed with water and EtOAc. The layers wereseparated and the organic layers washed with water (2×), brine, dried(MgSO₄), filtered and evaporated under vacuum. The residue was purifiedby column chromatography (normal phase, 50 g silica, Biotage SNAPcartridge KP-Sil, gradient 0% to 100% EtOAc in n-hexane) to give thedesired compound (280 mg).

LCMS: m/z 144.66 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 6.71 (dd, J=3.3, 0.9 Hz, 1H) 7.66 (d,J=8.4 Hz, 1H) 7.92 (d, J=3.3 Hz, 1H) 7.98 (dd, J=8.4, 0.8 Hz, 1H) 11.87(br. s., 1H).

(2) Intermediate 60: 3-Iodo-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

To a solution of 1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (Intermediate59), (280 mg) and DMF (4.6 mL) was added potassium hydroxide (417 mg)followed by iodine (596 mg) then the reaction mixture stirred at rt for60 min. A mixture of NaHSO₃ (Na₂S₂O₅) (195 mg), water (29 mL) and 28-30%ammonium hydroxide (2 mL) was added to the reaction mixture, which wasthen cooled in an ice-bath. The precipitate was filtered, washed withice-cold water and dried under high vacuum to give the desired compound(292 mg). The aqueous phase was extracted with EtOAc (3×), the combinedorganic extracts washed with brine (3×), dried (MgSO₄), filtered andevaporated under vacuum to give more of the desired compound (101 mg).

LCMS: m/z 270.38 [M+H]⁺.

(3) Intermediate 61: tert-Butyl5-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a suspension of 3-iodo-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile(Intermediate 60), (393 mg) and 4-dimethylaminopyridine (23.2 mg)stirred at rt in DCM (3.6 mL) was added dropwise a solution ofdi-t-butyldicarbonate (478 mg) in DCM (30 mL) then the reaction mixturestirred for 30 min. The solvent was evaporated and the residue purifiedby column chromatography (normal phase, 25 g silica, Biotage SNAPcartridge KP-Sil, gradient 0% to 50% EtOAc in n-hexane) to give thedesired compound (490 mg).

LCMS: m/z 370.3 [M+H]⁺.

(4) Intermediate 62: tert-Butyl5-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 5-cyano-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 61), (490 mg), palladium (II) acetate (8.9 mg), XantPhos(46.1 mg), (1S,2S)-2-aminocyclohexanol hydrochloride (302 mg), toluene(12.0 mL) and TEA (0.56 mL) were placed in a microwave tube with a COballoon. The microwave tube was purged with CO then heated to 80° C.overnight. The reaction mixture was diluted with EtOAc and the remainingsolid in the reaction flask was dissolved/suspended in a small amount ofTHF (˜2 mL) by sonication then added to the EtOAc organic phases thenthe combined organic phases washed with water (2×) then brine, dried(MgSO₄), filtered and evaporated under vacuum to give the crude product,which was used as such for Boc removal.

LCMS: m/z 385.58 [M+H]⁺ and m/z 285.52 [M+H-Boc]⁺.

(5) Intermediate 63:5-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of tert-butyl5-cyano-3-(((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 62), (510 mg), DCM (5.2 mL) and TFA (2.6 mL) were stirredat rt for 1.5 h. The solvent was evaporated and the residue was purifiedby column chromatography (normal phase, 28 g amino silica, Biotage SNAPcartridge KP-Sil, gradient 0% to 100% EtOAc in n-hexane) to give thedesired compound (323 mg).

LCMS: m/z 285.56 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 1.32 (d, J=6.5 Hz, 4H) 1.53-1.72 (m, 2H)1.88 (br. s., 1H) 2.05 (d, J=9.3 Hz, 1H) 3.44 (br. s., 1H) 3.73 (d,J=8.2 Hz, 1H) 7.80 (d, J=8.3 Hz, 1H) 8.10 (d, J=8.4 Hz, 1H) 8.29 (d,J=7.5 Hz, 1H) 8.42 (s, 1H).

Intermediate 66: Synthesis of1-(2-Fluoro-4-(6-methylpyridin-2-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

(1) Intermediate 64: 2-Fluoro-4-(6-methylpyridin-2-yl)benzaldehyde

Two separate reaction vessels, each containing a mixture of K₂CO₃ (823mg), 2-bromo-6-methylpyridine (614 mg) in toluene (5 mL) and water (2.5mL) were purged with nitrogen. To each vessel was addedPd(dppf)Cl₂.CH₂Cl₂ (242 mg) followed by (3-fluoro-4-formylphenyl)boronicacid (500 mg), the mixtures were further purged with nitrogen, beforebeing heated at 90° C. for 2 h. Once cooled, the two reaction mixtureswere combined, water was added and the reaction mixture extracted withEtOAc (3×). The organic phases were combined, dried (Na₂SO₄), filteredand evaporated under vacuum. The crude product was purified by columnchromatography (silica), eluting with 4:96 EtOAc/hexanes to afford thetitle compound (470 mg).

¹H NMR (400 MHz, DMSO-d₆) ppm 2.57 (s, 3H), 7.34 (d, J=7.6 Hz, 1H),7.82-7.89 (m, 1H), 7.90-8.01 (m, 2H), 8.05-8.19 (m, 2H), 10.26 (s, 1H)

(2) Intermediate 65: 2-(4-(Bromomethyl)-3-fluorophenyl)-6-methylpyridinehydrobromide

Sodium borohydride (123 mg) was added to a solution of2-fluoro-4-(6-methylpyridin-2-yl)benzaldehyde (Intermediate 64), (470mg) in methanol (10 mL) at 0° C. The reaction mixture was stirred for 2hours at a temperature between 10° C.-20° C. The reaction mixture wasconcentrated under vacuum before being diluted with water (15 mL). Theproduct was extracted with EtOAc (30 mL). The organic phase was dried(Na₂SO₄), filtered, and evaporated under vacuum to afford(2-fluoro-4-(6-methylpyridin-2-yl)phenyl)methanol (450 mg) of sufficientpurity to be used in the next step as such.

LCMS: m/z 218.09 [M+H]⁺.

(2-fluoro-4-(6-methylpyridin-2-yl)phenyl)methanol (450 mg) was dissolvedin 48% aq. hydrogen bromide solution (9 mL) and heated at 80-90° C. for2 h. The reaction mixture was concentrated under vacuum with residualsolvent removed by sequential azeotrope vacuum evaporation with CH₂Cl₂(1×) then toluene (2×). The title compound, isolated as a hydrogenbromide salt, was further dried under vacuum to yield the desiredcompound (620 mg) which was taken on as such.

LCMS: m/z 281.98 [M+H]⁺

(3) Intermediate 66:1-(2-Fluoro-4-(6-methylpyridin-2-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

To a mixture of 3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 1), (350mg) and potassium carbonate (791 mg) in DMF (8 mL) stirred at 0° C.under nitrogen was added2-(4-(bromomethyl)-3-fluorophenyl)-6-methylpyridine hydrobromide(Intermediate 65), (620 mg). The reaction mixture was allowed to warm tort and was stirred overnight. Water (50 mL) was added to the reactionmixture and the reaction mixture was extracted with EtOAc (100 mL). Theorganic phase was washed with brine (75 mL), dried (Na₂SO₄), filteredand evaporated under vacuum. The crude product was purified by columnchromatography (silica) eluting with 28:72 EtOAc:hexanes to afford thetitle compound (580 mg) which was taken on as such.

LCMS: m/z 444.11 [M+H]⁺.

Intermediate 69:1-(2-Fluoro-4-(2-methylpyridin-4-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

(1) Intermediate 67: 2-Fluoro-4-(2-methylpyridin-4-yl)benzaldehyde

Into two separate reaction vessels, each containing a mixture of K₂CO₃(823 mg), 4-bromo-2-methylpyridine (614 mg) in toluene (5 mL) and water(2.5 mL) were purged with nitrogen. To each vessel was addedPd(dppf)Cl₂.CH₂Cl₂ (242 mg) followed by (3-fluoro-4-formylphenyl)boronicacid (500 mg), the mixtures were further purged with nitrogen, beforebeing heated at 90° C. for 2 h. Once cooled, the two reaction mixtureswere combined, water was added and the reaction mixture extracted withEtOAc (3×). The organic phases were combined, dried (Na₂SO₄), filteredand evaporated under vacuum. The crude product was purified by columnchromatography (silica), eluting with 3:7 EtOAc/hexanes to afford thetitle compound (700 mg).

LCMS: m/z 216.09 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 2.55 (s, 3H), 7.63 (dd, J=5.5, 1.8 Hz,1H), 7.73 (d, J=1.2 Hz, 1H), 7.82-7.88 (m, 1H), 7.91 (dd, J=12.2, 1.5Hz, 1H), 7.94-8.00 (m, 1H), 8.57 (d, J=5.2 Hz, 1H), 10.26 (s, 1H)

(2) Intermediate 68: 4-(4-(Bromomethyl)-3-fluorophenyl)-2-methylpyridinehydrobromide

Sodium borohydride (0.184 g) was added to a solution of2-fluoro-4-(2-methylpyridin-4-yl)benzaldehyde (Intermediate 67), (700mg) in methanol (15 mL). The reaction mixture was stirred for 2 hours ata temperature between 0° C.-5° C. The reaction mixture was concentratedunder vacuum before being diluted with water (25 mL). The product wasextracted with EtOAc (35 mL). The organic phase was dried (Na₂SO₄),filtered, and evaporated under vacuum to afford(2-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanol (700 mg) of sufficientpurity to be used in the next step.

LCMS: m/z 218.19 [M+H]⁺.

(2-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanol (700 mg) was dissolvedin 48% aq. hydrogen bromide solution (14 mL) and heated at 90° C. for 2h. The reaction mixture was concentrated under vacuum with residualsolvent removed by sequential azeotrope vacuum evaporation with CH₂Cl₂(1×) then toluene (2×). The title compound, isolated as a hydrogenbromide salt, was further dried under vacuum and taken on as such.

LCMS: m/z 282.18 [M+H]⁺.

(3) Intermediate 69:1-(2-Fluoro-4-(2-methylpyridin-4-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

To a mixture of 3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 1), (300mg) and potassium carbonate (678 mg) in DMF (5 mL) stirred at 0° C.under nitrogen was added4-(4-(bromomethyl)-3-fluorophenyl)-2-methylpyridine hydrobromide(Intermediate 68), (531 mg). The reaction mixture was allowed to warm tort and was stirred overnight. Water (35 mL) was added to the reactionmixture and the reaction mixture was extracted with EtOAc (2×35 mL). Theorganic phases were combined, washed with brine (40 mL), dried (Na₂SO₄),filtered and evaporated under vacuum. The crude product was purified bycolumn chromatography (silica) eluting with 80:20 EtOAc:hexanes toafford the title compound (480 mg).

LCMS: m/z 444.16 [M+H]⁺.

Intermediate 72: Synthesis of1-((4′-Fluoro-[1,1′-biphenyl]-4-yl)methyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

(1) Intermediate 70: 4-Fluoro-4′-methyl-1,1′-biphenyl

A solution of (4-fluorophenyl)boronic acid (2.5 g) in toluene (15 mL)was purged with nitrogen. To which, was added Pd(PPh₃)₄ (4.12 g) and themixture purged further before the addition of 1-bromo-4-methylbenzene(3.67 g) followed by the addition of sodium carbonate (5.68 g) in water(10 mL). The mixture was further purged before being heated at 85° C.for 2 h. Once cooled, water was added and the reaction mixture extractedwith EtOAc (2×). The organic phases were combined, dried, filtered andevaporated under vacuum. The crude product was purified by columnchromatography (silica), eluting with 1:19 EtOAc/hexanes to afford thetitle compound (1.8 g) which was taken on as such.

(2) Intermediate 71: 4-Fluoro-4′-methyl-1,1′-biphenyl

N-Bromosuccinimide (2 g) was added to a solution of4-fluoro-4′-methyl-1,1′-biphenyl (Intermediate 70), (1.8 g) in CHCl₃ (90mL) followed by the addition of AIBN (300 mg). The reaction mixture washeated under reflux overnight. Once cooled, water was added and thecrude product extracted with CHCl₃. The organic phase was dried,filtered and evaporated under vacuum. The crude product was purified bycolumn chromatography (silica), eluting with 1:99 EtOAc/hexanes toafford the title compound (850 mg).

¹H NMR (400 MHz, CDCl₃) ppm 4.56 (s, 2H), 7.10-7.18 (m, 2H), 7.45-7.50(m, 2H), 7.50-7.59 (m, 4H).

(3) Intermediate 72:1-((4′-Fluoro-[1,1′-biphenyl]-4-yl)methyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine

Sodium hydride (140 mg, 60% dispersion in mineral oil) was added to asolution of 3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 1), (700 mg)in dimethyl acetamide (7 mL) at 0° C. The RM was allowed to warm to rtand was stirred for 30 min. To which, was added4-fluoro-4′-methyl-1,1′-biphenyl (Intermediate 71), (840 mg) and thereaction mixture stirred for a further 1 h. The reaction was quenchedwith water (20 mL) and extracted with EtOAc (3×20 mL). The organicphases were combined, dried (Na₂SO₄), filtered, and evaporated undervacuum. The crude product was purified by column chromatography(silica), eluting with 20:80 EtOAc/hexanes to afford the title compound(700 mg).

LCMS: m/z 429.04 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 5.51 (s, 2H), 7.21 (dd, J=8.2, 4.6 Hz,1H), 7.23-7.30 (m, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.54-7.62 (m, 2H),7.62-7.69 (m, 2H), 8.00 (dd, J=8.2, 1.2 Hz, 1H), 8.09 (s, 1H), 8.40 (dd,J=4.4, 1.4 Hz, 1H)

Intermediate 73: Synthesis ofN-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (200 mg),triethylamine (0.688 mL), BOP (818 mg), HATU (563 mg) and DMF (4.8 mL)were stirred for 15 min. (1R,2R)-2-aminocyclohexanol hydrochloride (281mg) was added and the reaction mixture left to stir overnight. Thereaction mixture was purified by preparative LCMS to give the desiredcompound (133 mg).

LCMS: m/z 260.1 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) ppm 1.15-1.57 (m, 6H) 1.75 (d, J=9.5 Hz, 2H)2.03-2.14 (m, 2H) 3.53 (td, J=9.8, 4.3 Hz, 1H) 3.79-3.91 (m, 1H) 7.13(dd, J=8.3, 4.6 Hz, 1H) 7.72 (dd, J=8.2, 1.3 Hz, 1H) 8.04 (s, 1H) 8.41(dd, J=4.8, 1.3 Hz, 1H) 9.12 (d, J=6.8 Hz, 1H)

Intermediate 74: tert-Butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 3-iodo-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 11), (750 mg), trans-4-aminotetrahydro-2H-pyran-3-ol (CASno. 215940-92-4), (245 mg), palladium (II) acetate (114 mg), XantPhos(73 mg), toluene (13.4 mL) and TEA (0.88 mL) were combined. The reactionmixture was purged with CO then heated to 80° C. over a weekend. Thereaction was cooled to rt and poured onto EtOAc, the remaining solid inthe reaction flask was sonicated with a small amount of THF and theslurry added to the EtOAc organic phases. The combined organic phaseswere washed with water (2×) then brine and the combined aqueous phasesextracted with EtOAc (1×). The combined organic extracts were dried(MgSO₄), filtered and evaporated under vacuum to give the desiredcompound (786 mg), which was taken on crude.

LCMS: m/z 274.5 [M+H-BOC]⁺.

Intermediate 75: Synthesis of tert-Butyl7-chloro-3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 15), (820 mg), trans-4-aminotetrahydro-2H-pyran-3-ol (381mg), palladium (II) acetate (14.6 mg), XantPhos (75 mg), toluene (19.6mL) and TEA (0.91 mL) were combined. The reaction mixture was purgedwith CO then heated to 80° C. over a weekend. The reaction was cooled tort and poured onto EtOAc, the remaining solid in the reaction flask wassonicated with a small amount of THF and the slurry added to the EtOAcorganic phases. The combined organic phases were washed with water (2×)then brine and the combined aqueous phases extracted with EtOAc (1×).The combined organic extracts were dried (MgSO₄), filtered andevaporated under vacuum to give the desired compound (540 mg), which wastaken on crude.

LCMS: m/z 294.4 [M+H-BOC]⁺.

Intermediate 76: Synthesis of tert-Butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

A mixture of tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 2), (5.00 g), trans-4-aminotetrahydro-2H-pyran-3-olhydrochloride (1.86 g), Pd(OAc)₂ (82 mg), XantPhos (420 mg) and TEA(5.06 mL) in toluene (50 mL) was purged with CO then heated to 80° C.overnight. The reaction was cooled to rt and poured onto EtOAc, theremaining solid in the reaction flask was sonicated with a small amountof THF and the slurry added to the EtOAc organic phases. The combinedorganic phases were washed with water (2×) then brine and the combinedaqueous phases extracted with EtOAc (1×). The combined organic extractswere dried (MgSO₄), filtered and evaporated under vacuum to give thedesired compound (9.36 g), which was taken on crude.

LCMS: m/z 260.5 [M+H-BOC]⁺.

Intermediate 78: Synthesis of7-chloro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 77: tert-Butyl7-chloro-3-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 15), (200 mg), Pd(OAc)₂ (3.6 mg),(3R,4S)-4-aminotetrahydropyran-3-ol hydrochloride (Purchased fromNetChem, Inc.), (81 mg), XantPhos (18.3 mg), toluene (6 mL) and TEA(0.22 mL) was added to a three-neck round-bottomed flask fitted with areflux condenser. This was purged with CO and stirred at 80° C.overnight under a CO balloon. The reaction mixture was allowed to coolto rt and then diluted with EtOAc and filtered through celite andconcentrated in vacuo. The residue was purified by column chromatographyto afford the desired compound (104 mg).

LCMS: m/z 396.13 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.67 (s, 9H) 1.87-2.10 (m, 2H) 3.60 (td,J=11.3, 2.8 Hz, 1H) 3.70 (s, 1H) 3.85-4.07 (m, 3H) 4.40 (td, J=5.4, 2.9Hz, 1H) 7.32-7.37 (m, 1H) 8.45 (d, J=5.1 Hz, 1H) 8.50 (s, 1H) 9.42 (d,J=8.0 Hz, 1H)

(2) Intermediate 78:7-chloro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl7-chloro-3-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 77), (100 mg) in MeOH (2 mL) was added HCl (4M solution in1,4-dioxane), (10 mL) at rt and stirred for 2d. The reaction mixture wasconcentrated in vacuo to afford P1 as a colorless solid withoutpurification (74 mg).

LCMS: m/z 296.08 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 1.58 (dd, J=12.9, 3.71 Hz, 1H) 1.83-2.02(m, 1H) 3.34-3.57 (m, 2H) 3.62-3.85 (m, 3H) 4.06-4.18 (m, 1H) 7.52-7.67(m, 1H) 8.46 (d, J=5.5 Hz, 1H) 8.51-8.68 (m, 1H) 8.77 (d, J=7.8 Hz, 1H)13.11 (br. s., 1H)

Intermediate 80: Synthesis of7-chloro-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1) Intermediate 79: tert-Butyl7-chloro-3-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

tert-Butyl 7-chloro-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 15), (200 mg), Pd(OAc)₂ (3.6 mg),(3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (Purchased fromNetChem, Inc.), (81 mg), XantPhos (18.3 mg), toluene (6 mL) and TEA(0.22 mL) was added to a three-neck round-bottomed flask fitted with areflux condenser. This was purged with CO and stirred at 80° C.overnight under a CO balloon. The reaction mixture was allowed to coolto rt and then diluted with EtOAc and filtered through celite andconcentrated in vacuo. The residue was purified by column chromatographyto afford the desired compound (113 mg).

LCMS: m/z 396.13 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.67 (s, 9H) 1.89-2.09 (m, 2H) 3.60 (td,J=11.3, 2.9 Hz, 1H) 3.68 (d, J=10.7 Hz, 1H) 3.89-4.05 (m, 3H) 4.39(dddd, J=10.7, 8.0, 5.0, 2.8 Hz, 1H) 7.34 (d, J=5.1 Hz, 1H) 8.45 (d,J=5.3 Hz, 1H) 8.50 (s, 1H) 9.42 (d, J=8.0 Hz, 1H)

(2) Intermediate 80:7-chloro-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl7-chloro-3-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 79), (100 mg) in MeOH (2 mL) was added HCl (4M solution in1,4-dioxane), (10 mL) at rt and stirred for 2d. The reaction mixture wasconcentrated in vacuo to afford P1 as a colorless solid withoutpurification (74 mg).

LCMS: m/z 296.08 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) ppm 1.58 (d, J=11.3 Hz, 1H) 1.81-2.03 (m, 1H)3.33-3.57 (m, 2H) 3.60-3.89 (m, 3H) 4.12 (br. s., 1H) 7.57 (br. s., 1H)8.45 (d, J=3.5 Hz, 1H) 8.45-8.67 (m, 1H) 8.67-8.87 (m, 1H) 13.07 (br.s., 1H)

Compound Examples 1-105 Example 1:N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (100 mg), 1-(chloromethyl)-4-methylbenzene (60 mg) andcesium carbonate (289 mg) was added DMF (4 mL) and left to stir at rtfor 90 min. The crude product was purified by prep. LC-MS to give thedesired compound (88 mg).

LCMS: m/z 364.65 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.20-1.88 (m, 6H) 2.10-2.21 (m, 2H) 2.34 (s,3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.80-4.02 (m, 1H) 4.54 (br. s., 1H)5.30 (s, 2H) 6.99-7.10 (m, 2H) 7.10-7.22 (m, 3H) 7.50-7.72 (m, 1H) 8.09(s, 1H) 8.39-8.59 (m, 1H) 9.05 (d, J=6.1 Hz, 1H)

Example 2:1-(3,5-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (80 mg), 1-(bromomethyl)-3,5-difluorobenzene (77 mg)and cesium carbonate (231 mg) was added DMF (3 mL) and left to stir atrt over the weekend. The crude product was diluted with MeOH andpurified using an SCX-2 cartridge (washed sequentially with MeOH, H₂O,MeOH and product eluted using 2 M methanolic ammonia). The solution wasevaporated under vacuum to give a solid which was dissolved in DCM andpurified using column chromatography (normal phase, 25 g, Biotage SNAPcartridge KP-Sil, 25 mL/min, gradient 0-100% EtOAc in n-hexane) to givethe desired compound (70 mg)

LCMS: m/z 386.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.15-1.67 (m, 4H) 1.72-1.91 (m, 2H)2.07-2.23 (m, 2H) 3.59 (td, J=9.9, 4.5 Hz, 1H) 3.92 (dddd, J=11.5, 9.4,7.0, 4.4 Hz, 1H) 5.34 (s, 2H) 6.57-6.69 (m, 2H) 6.77 (tt, J=8.8, 2.3 Hz,1H) 7.21 (dd, J=8.3, 4.8 Hz, 1H) 7.50-7.69 (m, 1H) 8.13 (s, 1H) 8.54(dd, J=4.8, 1.2 Hz, 1H) 9.04 (d, J=6.6 Hz, 1H)

Example 3:1-(2,5-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (80 mg), 2-(bromomethyl)-1,4-difluorobenzene (77 mg)and cesium carbonate (231 mg) was added DMF (3 mL) and left to stir atrt over the weekend. The crude product was purified by prep. LC-MS togive the desired compound (68 mg).

LCMS: m/z 386.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.10-1.64 (m, 4H) 1.67-1.90 (m, 2H) 2.14 (d,J=11.6 Hz, 2H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.81-4.00 (m, 1H) 5.36 (s,2H) 6.57-6.77 (m, 1H) 6.88-7.05 (m, 1H) 7.05-7.14 (m, 1H) 7.22 (dd,J=8.3, 4.7 Hz, 1H) 7.69 (d, J=8.3 Hz, 1H) 8.11 (s, 1H) 8.53 (d, J=4.4Hz, 1H) 9.04 (d, J=6.2 Hz, 1H)

Example 4:1-(3-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (80 mg), 1-(bromomethyl)-3-fluorobenzene (70 mg) andcesium carbonate (231 mg) was added DMF (3.2 mL) and left to stir at rtfor 90 min. The crude product was diluted with MeOH and purified using aSCX-2 cartridge (washed sequentially with MeOH, H₂O, MeOH and producteluted using 2 M methanolic ammonia). The solution was evaporated undervacuum to give a solid which was further purified by prep. LC-MS (1×3 mLinjection) to give the desired compound (62 mg).

LCMS: m/z 368.60 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.04-1.72 (m, 4H) 1.79 (m, 2H) 2.14 (d,J=9.8 Hz, 2H) 3.58 (td, J=9.9, 4.3 Hz, 1H) 3.81-4.02 (m, 1H) 4.12-4.79(br. s., 1H) 5.35 (s, 2H) 6.84 (d, J=9.1 Hz, 1H) 6.93 (d, J=7.6 Hz, 1H)6.97-7.10 (m, 1H) 7.19 (dd, J=8.2, 4.8 Hz, 1H) 7.28-7.41 (m, 1H) 7.60(d, J=8.2 Hz, 1H) 8.12 (s, 1H) 8.52 (d, J=4.7 Hz, 1H) 9.05 (d, J=6.1 Hz,1H)

Example 5:1-(4-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (3 g) and cesium carbonate (8.67 g) in DMF (82 mL)stirred at rt under nitrogen was added 1-(bromomethyl)-4-fluorobenzene(2.406 g) in DMF (5 mL) and the reaction mixture stirred for 6.5 h thenleft to stand overnight without stirring. The reaction was then dilutedwith EtOAc, washed with water (3×), brine, dried (MgSO₄), filtered andevaporated under vacuum. The residue was purified by columnchromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50mL per min, gradient 0% to 100% EtOAc in n-hexane, followed by 0-10%MeOH in EtOAc). The eluted products were combined and purified by columnchromatography (normal phase, 110 g, Biotage SNAP cartridge KP-NH, 50 mLper min, gradient 0% to 100% EtOAc in n-hexane) to give the titlecompound (2.80 g).

LCMS: m/z 368.59 [M+H]⁺.

¹H NMR (600 MHz, DMSO-d₆) ppm 1.21-1.39 (m, 4H) 1.59-1.70 (m, 2H) 1.89(d, J=10.0 Hz, 1H) 2.00-2.08 (m, 1H) 3.42 (tt, J=8.7, 4.4 Hz, 1H)3.69-3.78 (m, 1H) 4.78 (d, J=5.0 Hz, 1H) 5.52 (s, 2H) 7.14-7.19 (m, 2H)7.27 (dd, J=8.2, 4.7 Hz, 1H) 7.38 (dd, 5.6 Hz, 2H) 8.08 (dd, J=8.4, 1.0Hz, 1H) 8.40 (s, 1H) 8.49 (dd, J=4.7, 0.9 Hz, 1H) 8.75 (d, J=7.6 Hz,1H).

Example 6:1-(4-Fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (100 mg), 4-(bromomethyl)-1-fluoro-2-methylbenzene (86mg) and cesium carbonate (289 mg) was added DMF (4 mL) and left to stirat rt for 90 min. The crude product was diluted with MeOH and purifiedusing an SCX-2 cartridge (washed sequentially with MeOH, H₂O, MeOH andproduct eluted using 2 M methanolic ammonia). The solution wasevaporated under vacuum to give the desired compound (150 mg).

LCMS: m/z 382.64 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.12-1.90 (m, 6H) 2.07-2.19 (m, 2H) 2.23 (d,J=1.5 Hz, 3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.78-4.03 (m, 1H) 4.49 (br.s., 1H) 5.27 (s, 2H) 6.86-7.07 (m, 3H) 7.18 (dd, J=8.3, 4.8 Hz, 1H)7.52-7.73 (m, 1H) 8.08 (s, 1H) 8.50 (dd, 1.0 Hz, 1H) 9.04 (d, J=6.0 Hz,1H)

Example 7:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((2-methylthiazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (100 mg), 4-(chloromethyl)-2-methylthiazole (68 mg)and cesium carbonate (289 mg) was added DMF (4 mL) and left to stir atrt for 3 h. The crude product was diluted with MeOH and purified usingan SCX-2 cartridge (washing sequentially with MeOH, H₂O, MeOH andproduct eluted using 2 M methanolic ammonia). The solution wasevaporated under vacuum to give a solid which was further purified byprep. LC-MS to give the desired compound (87 mg).

LCMS: m/z 371.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.05-1.94 (m, 6H) 2.11-2.25 (m, 2H) 2.70 (s,3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.82-4.00 (m, 1H) 4.14-4.88 (br. s.,1H) 5.41 (s, 2H) 6.80 (s, 1H) 7.21 (dd, J=8.3, 4.7 Hz, 1H) 7.77 (d,J=8.2 Hz, 1H) 8.13 (s, 1H) 8.51 (d, J=4.7 Hz, 1H) 9.05 (d, J=6.1 Hz, 1H)

Example 8:1-(2,3-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (100 mg), 1-(bromomethyl)-2,3-difluorobenzene (96 mg)and cesium carbonate (289 mg) was added DMF (4 mL) and left to stir atrt for 90 min. The crude product was diluted with MeOH and purifiedusing an SCX-2 cartridge (washed sequentially with MeOH, H₂O, MeOH andproduct eluted using 2 M methanolic ammonia). The solution wasevaporated under vacuum to give the desired compound (130 mg).

LCMS: m/z 386.58 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.19-2.18 (m, 8H) 3.57 (td, J=10.0, 4.3 Hz,1H) 3.74-4.01 (m, 1H) 4.03-4.91 (br. s., 1H) 5.42 (s, 2H) 6.79 (t, J=6.7Hz, 1H) 6.93-7.09 (m, 1H) 7.10-7.20 (m, 1H) 7.23 (dd, J=8.3, 4.8 Hz, 1H)7.72 (d, J=8.3 Hz, 1H) 8.14 (s, 1H) 8.53 (d, J=4.7 Hz, 1H) 9.04 (d,J=6.4 Hz, 1H)

Example 9:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (120 mg), 1-(bromomethyl)-4-(trifluoromethoxy)benzene(130 mg) and cesium carbonate (347 mg) was added DMF (4.8 mL) and leftto stir at rt overnight.

The crude product was purified by prep. LC-MS to give the desiredcompound (126 mg).

LCMS: m/z 434.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.88-1.97 (m, 6H) 2.14 (d, J=10.1 Hz, 2H)3.58 (td, J=9.8, 4.4 Hz, 1H) 3.77-4.01 (m, 1H) 5.37 (s, 2H) 6.92-7.25(m, 5H) 7.62 (d, J=8.2 Hz, 1H) 8.12 (s, 1H) 8.53 (d, J=4.8 Hz, 1H) 9.04(d, J=6.2 Hz, 1H)

¹⁹F NMR (377 MHz, CDCl₃) ppm −57.93 (s, 3F))

Example 10:1-(4-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (700 mg) in DMF (25 mL) stirred under nitrogen at rtwas added Cs₂CO₃ (1919 mg) followed by 1-(bromomethyl)-4-fluorobenzene(0.319 mL) the reaction was stirred at rt under nitrogen overnight, atwhich point LC-MS indicated completion. The reaction was filtered andthe filtrate was reduced in vacuo, then purified by columnchromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mLper min, gradient 20% to 100% EtOAc in n-hexane, then 0-15% MeOH inEtOAc) to give the desired product (0.370 g).

LCMS: m/z 382.60 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.96-1.97 (m, 6H) 1.98-2.17 (m, 2H) 2.51 (s,3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.80-4.08 (m, 1H) 4.47 (br. s., 1H)5.53 (s, 2H) 6.84-6.96 (m, 3H) 6.96-7.09 (m, 2H) 8.02 (s, 1H) 8.34 (d,J=4.8 Hz, 1H) 9.26 (d, J=6.1 Hz, 1H)

Example 11:1-(2,3-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (150 mg) in DMF (5.5 mL) stirred under nitrogen at rtwas added Cs₂CO₃ (411 mg) followed by1-(bromomethyl)-2,3-difluorobenzene (0.070 mL). The reaction was stirredat rt under nitrogen overnight, at which point LC-MS indicatedcompletion. The reaction was filtered and the filtrate was reduced invacuo, then purified by column chromatography (normal phase, 10 g,Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 50% to 100% EtOAcin n-hexane, then 0-15% MeOH in EtOAc) to give the desired product (102mg).

LCMS: m/z 400.61 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.19-1.61 (m, 4H) 1.70-1.84 (m, 2H)2.07-2.17 (m, 2H) 2.50 (s, 3H) 3.56 (td, J=9.8, 4.5 Hz, 1H) 3.79-3.94(m, 1H) 4.56 (br. s., 1H) 5.58 (s, 2H) 6.28 (t, J=6.9 Hz, 1H) 6.86-6.99(m, 2H) 7.11 (q, J=8.4 Hz, 1H) 7.99 (s, 1H) 8.33 (d, J=4.7 Hz, 1H) 9.24(d, J=6.4 Hz, 1H).

Example 12:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-methoxybenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (150 mg) in DMF (5 mL) stirred under nitrogen at rtwas added Cs₂CO₃ (411 mg) followed by 1-(bromomethyl)-4-methoxybenzene(110 mg). The reaction was stirred at rt under nitrogen overnight, atwhich point LC-MS indicated completion. The reaction was filtered andthe filtrate was reduced in vacuo, then purified by columnchromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mLper min, gradient 20% to 100% EtOAc in n-hexane, followed by 0-15% MeOHin EtOAc) to yield the desired compound (103 mg).

LCMS: m/z 394.65 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.21-1.62 (m, 4H) 1.77 (br. S., 2H) 2.13 (d,J=12.4, 2H) 2.53 (s, 3H) 3.56 (td, J=9.8, 4.5 Hz, 1H) 3.76 (s, 3H)3.82-3.94 (m, 1H) 4.68 (br. s., 1H) 5.46 (s, 2H) 6.77-6.92 (m, 5H)7.95-8.03 (m, 1H) 8.31 (d, J=4.7 Hz, 1H) 9.27 (d, J=6.4 Hz, 1H)

Example 13:1-(3-Fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg) in DMF (3.6 mL) stirred under nitrogen at rtwas added Cs₂CO₃ (302 mg) followed by4-(bromomethyl)-2-fluoro-1-methoxybenzene (88 mg). The reaction wasstirred at rt under nitrogen overnight, at which point LC-MS indicatedcompletion. The reaction was filtered and the filtrate was reduced invacuo, then purified by column chromatography (normal phase, 10 g,Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 50% to 100% EtOAcin n-hexane, then 0-15% MeOH in EtOAc) to give the desired product, (102mg).

LCMS: m/z 412.63 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.84 (m, 6H) 2.15 (d, J=10.8 Hz, 2H)2.57 (s, 3H) 3.64 (br. s., 1H) 3.80-3.95 (m, 1H) 3.87 (s, 3H) 5.51 (s,2H) 6.64 (d, J=8.2 Hz, 1H) 6.73 (d, J=11.7 Hz, 1H) 6.83-7.02 (m, 2H)8.30-8.46 (m, 1H) 9.27 (d, J=6.4 Hz, 1H)

Example 14:7-Chloro-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (140 mg), 1-(bromomethyl)-4-fluorobenzene (108 mg)and cesium carbonate (357 mg) was added DMF (4.9 mL) and left to stir atrt for 1 h 10 min. The crude product was purified by prep. LC-MS (1×3 mLinjection) to give the desired compound (111 mg).

LCMS: m/z 402.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.05-2.60 (m, 8H) 3.56 (td, J=9.9, 4.3 Hz,1H) 3.76-4.07 (m, 1H) 5.50-5.91 (m, 2H) 6.89-7.13 (m, 4H) 7.19 (d, J=5.0Hz, 1H) 8.09 (s, 1H) 8.36 (d, J=5.1 Hz, 1H) 9.04 (d, J=6.1 Hz, 1H)

Example 15:7-Chloro-1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (220 mg), 1-(bromomethyl)-2,3-difluorobenzene (171mg) and cesium carbonate (561 mg) was added DMF (3 mL) and left to stirat rt for 3 h. The crude product was purified by prep. LC-MS thenazeotroped with DCM to remove the residual AcOH to give the the titlecompound (121 mg).

LCMS: m/z 420.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.09-1.62 (m, 4H) 1.80 (d, J=9.3 Hz, 2H)2.10-2.22 (m, 2H) 3.56 (td, J=9.9, 4.5 Hz, 1H) 3.76-4.01 (m, 1H)5.62-5.95 (m, 2H) 6.50 (t, J=6.8 Hz, 1H) 6.92-7.05 (m, 1H) 7.15 (q,J=8.6 Hz, 1H) 7.20 (d, J=5.0 Hz, 1H) 8.10 (s, 1H) 8.38 (d, J=5.0 Hz, 1H)9.03 (d, J=6.0 Hz, 1H)

Example 16:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (200 mg), 2-(bromomethyl)-6-methylpyridine (139 mg)and cesium carbonate (510 mg) was added DMF (3 mL) and left to stir atrt overnight. The crude product was diluted with EtOAc (150 mL) andwashed with water (2×40 mL) and brine (40 mL), dried over MgSO₄ filteredand evaporated under vacuum to give a solid which was purified by columnchromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25mL/min, gradient 20-100% EtOAc in n-hexane) to give the desired compound(143 mg).

LCMS: m/z 399.61 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.10-1.94 (m, 6H) 2.14 (d, J=11.5 Hz, 2H)2.58 (s, 3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.82-4.01 (m, 1H) 4.30 (br.s., 1H) 5.67-5.94 (m, 2H) 6.49 (d, J=7.7 Hz, 1H) 7.08 (d, J=7.7 Hz, 1H)7.18 (d, J=5.1 Hz, 1H) 7.49 (t, J=7.8 Hz, 1H) 8.14 (s, 1H) 8.36 (d,J=5.1 Hz, 1H) 9.05 (d, J=6.5 Hz, 1H)

Example 17:7-Chloro-1-((5-fluoropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of 5-fluoro-2-hydroxymethylpyridine (purchased from ArkPharm Inc.), (250 mg) in anhydrous DCM (8.4 mL) stirred at rt undernitrogen, was added thionyl chloride (0.29 mL). The reaction was stirredat rt overnight, at which point LC-MS indicated presence of the product.The reaction was then concentrated in vacuo and re-dissolved in DCM (10mL) and concentrated in vacuo again to give2-(chloromethyl)-5-fluoropyridine hydrochloride (102 mg), which wasadded to a mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), and cesium carbonate (383 mg) in DMF (3 mL)and left to stir at rt over the weekend. The crude product was purifiedby prep. LC-MS to give the desired compound (129 mg).

LCMS: m/z 403.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.62 (m, 4H) 1.80 (d, J=9.5 Hz, 2H)2.07-2.18 (m, 2H) 3.57 (td, J=9.9, 4.4 Hz, 1H) 3.84-3.99 (m, 1H)5.69-5.95 (m, 2H) 6.86 (dd, J=8.6, 4.0 Hz, 1H) 7.19 (d, J=5.1 Hz, 1H)7.34 (td, J=8.3, 2.8 Hz, 1H) 8.19 (br. s., 1H) 8.37 (d, J=5.1 Hz, 1H)8.43 (d, J=2.7 Hz, 1H) 9.04 (d, J=6.2 Hz, 1H)

¹⁹F NMR (377 MHz, CDCl₃) ppm −127.69 (s, 1F)

Example 18:1-(4-Fluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

1-(4-Fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 18),(150 mg), palladium (II) acetate (2.9 mg), XantPhos (14.8 mg),(trans-2-aminocyclohexyl)methanol (83 mg), toluene (2.7 mL) and TEA(0.18 mL) were placed in a microwave tube fitted with a CO balloon. Themicrowave tube was purged with CO then heated to 80° C. overnight atwhich point LC-MS indicated completion. The reaction was then filteredthrough celite, washing with EtOAc. The residue at the bottom of theflask was sonicated in EtOAc and filtered through the same celite pad.The filtrate was reduced in vacuo. The residue was dissolved in MeOH (5mL) and loaded onto an SCX-2 cartridge, washing with 5 CV MeOH, theneluting with 5 CV 2M NH3/MeOH. The basic fractions were combined andreduced in vacuo. The residue was purified by column chromatography(normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min,gradient 0% to 100% EtOAc in hexane followed by 0% to 10% MeOH in EtOAc)to yield the desired compound as a racemic mixture of trans isomers (46mg).

LCMS: m/z 382.58 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.17-1.49 (m, 3H) 1.51-1.90 (m, 5H)2.01-2.16 (m, 1H) 3.35 (d, J=7.2 Hz, 1H) 3.81 (dd, J=11.9, 1.8 Hz, 1H)3.92-4.05 (m, 1H) 4.41 (br. s., 1H) 5.24-5.36 (m, 2H) 6.97-7.21 (m, 5H)7.61 (d, J=8.2 Hz, 1H) 8.07 (s, 1H) 8.45-8.54 (m, 1H) 8.88 (d, J=8.4 Hz,1H)

Example 19:1-(4-Fluorobenzyl)-N-(trans-3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

1-(4-Fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 18),(50 mg), palladium (II) acetate (1.0 mg), XantPhos (4.9 mg),trans-3-methyltetrahydro-2H-pyran-4-amine hydrochloride (WO 2010/063634A1), (25.8 mg), toluene (0.9 mL) and TEA (0.06 mL) were placed in amicrowave tube fitted with a CO balloon. The microwave tube was purgedwith CO then heated to 80° C. overnight at which point LC-MS indicatedcompletion. The reaction was then filtered through celite, washing withEtOAc. The residue at the bottom of the flask was sonicated in EtOAc andfiltered through the same celite pad. The filtrate was reduced in vacuo.The residue was dissolved in MeOH (5 mL) and loaded onto an SCX-2cartridge, washing with 5 CV MeOH, then eluting with 5 CV 2M NH3/MeOH.The basic fractions were combined and reduced in vacuo. The residue waspurified by column chromatography (normal phase, 25 g, Biotage SNAPcartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexanefollowed by 0% to 10% MeOH in EtOAc) to yield the desired compound as aracemic mixture of trans isomers (9 mg).

LCMS: m/z 368.55 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.97 (d, J=6.6 Hz, 3H) 1.66-1.95 (m, 2H)2.01-2.14 (m, 1H) 3.20 (t, J=11.1 Hz, 1H) 3.58 (td, J=11.9, 2.1 Hz, 1H)3.90-4.10 (m, 3H) 5.32 (s, 2H) 6.98-7.07 (m, 2H) 7.09-7.21 (m, 3H) 7.60(dd, J=8.3, 1.0 Hz, 1H) 8.09 (s, 1H) 8.52 (dd, J=4.7, 1.1 Hz, 1H) 8.88(d, J=8.4 Hz, 1H)

Example 20:1-(4-Fluorobenzyl)-N-(trans-2-methylcyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

1-(4-Fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 18),(150 mg), palladium (II) acetate (2.9 mg), XantPhos (14.8 mg),trans-2-methylcyclohexanamine, (purchased from J&W PharmLab.), (48.2mg), toluene (2.7 mL) and TEA (0.18 mL) were placed in a microwave tubefitted with a CO balloon. The microwave tube was purged with CO thenheated to 80° C. overnight at which point LC-MS indicated completion.The reaction was then filtered through celite, washing with EtOAc. Theresidue at the bottom of the flask was sonicated in EtOAc and filteredthrough the same celite pad. The filtrate was reduced in vacuo. Theresidue was dissolved in MeOH (5 mL) and loaded onto an SCX-2 cartridge,washing with 5 CV MeOH, then eluting with 5 CV 2M NH3/MeOH. The basicfractions were combined and reduced in vacuo. The residue was purifiedby column chromatography (normal phase, 25 g, Biotage SNAP cartridgeKP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane followed by0% to 10% MeOH in EtOAc) to yield the desired compound as a racemicmixture of trans isomers (52 mg).

LCMS: m/z 366.60 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.03 (d, J=6.5 Hz, 3H) 1.11-1.62 (m, 5H)1.64-1.86 (m, 3H) 2.07-2.16 (m, 1H) 3.70-3.83 (m, 1H) 5.29 (s, 2H)6.94-7.17 (m, 5H) 7.57 (d, J=8.2 Hz, 1H) 8.06 (s, 1H) 8.49 (d, J=4.5 Hz,1H) 8.76 (d, J=8.7 Hz, 1H).

Example 21:1-(4-Fluorobenzyl)-N-(1-(hydroxymethyl)cyclopentyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

(1-Aminocyclopentyl)methanol (49.1 mg),1-(4-fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (Intermediate 18),(150 mg), palladium (II) acetate (2.9 mg), XantPhos (14.8 mg) toluene(2.7 mL) and TEA (0.18 mL) were placed in a microwave tube fitted with aCO balloon. The microwave tube was purged with CO then heated to 80° C.overnight at which point LC-MS indicated completion. The reaction wasthen filtered through celite, washing with EtOAc. The residue at thebottom of the flask was sonicated in EtOAc and filtered through the samecelite pad. The filtrate was reduced in vacuo. The residue was dissolvedin MeOH (5 mL) and loaded onto an SCX-2 cartridge, washing with 5 CVMeOH, then eluting with 5 CV 2M NH3/MeOH. The basic fractions werecombined and reduced in vacuo. The residue was purified by columnchromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mLper min, gradient 0% to 100% EtOAc in hexane followed by 0% to 10% MeOHin EtOAc) to yield the desired compound (5 mg).

LCMS: m/z 368.57 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.66-2.10 (m, 8H) 3.80 (s, 2H) 5.32 (s, 2H)5.68-5.99 (m, 1H) 6.99-7.22 (m, 5H) 7.61 (d, J=8.3 Hz, 1H) 8.05 (s, 1H)8.52 (d, J=4.7 Hz, 1H) 9.32 (br. s., 1H)

Example 22:1-(2-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of palladium (II) acetate (3.0 mg) in toluene (2.6 mL) waspurged with nitrogen. To this mixture was added XantPhos (8.0 mg)followed by Na₂CO₃ (238 mg) and (1S,2S)-2-aminocyclohexanol (127 mg) andthe reaction was purged with nitrogen.1-(2-fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made by alkylationof Intermediate 1, using a method analogous to that described inIntermediate 18), (260 mg) was then added and the reaction was purgedwith CO gas for 5 min at rt and then stirred under CO at 85° C.overnight, at which point TLC indicated disappearance of SM. Thereaction was cooled to rt, diluted with EtOAc and filtered throughcelite. The filtrate was diluted with water and extracted 2× with EtOAc.Combined organic layers were dried over Na₂SO₄, filtered and reduced invacuo. The residue was purified by column chromatography, eluting with80-90% EtOAc/Hexane) to give an impure product, which was trituratedwith 4:1 pentane:Et₂O to give the desired compound (75 mg).

LCMS: m/z 368.24 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.25-1.49 (m, 4H) 1.59-1.72 (m, 2H)1.83-1.93 (m, 1H) 1.98-2.08 (m, 1H) 3.38-3.47 (m, 1H) 3.67-3.77 (m, 1H)4.80 (d, J=5.2 Hz, 1H) 5.61 (s, 2H) 7.12-7.42 (m, 5H) 8.07 (dd, J=8.4,1.2 Hz, 1H) 8.29 (s, 1H) 8.50 (dd, J=4.8, 1.2 Hz, 1H) 8.75 (d, J=7.6 Hz,1H)

Example 23:1-(4-Chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of palladium (II) acetate (3.0 mg) in toluene (3 mL) waspurged under nitrogen. To this mixture was added XantPhos (8.0 mg),followed by Na₂CO₃ (240 mg) and (1S,2S)-2-aminocyclohexanol (130 mg).1-(4-chlorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made by alkylationof Intermediate 1, using a method analogous to that described inIntermediate 18), (280 mg) was then added and the reaction was purgedwith CO gas and stirred under CO at 85° C. overnight, at which point TLCindicated disappearance of SM. The reaction was cooled to rt, dilutedwith water and extracted 2× with EtOAc. Combined organic layers werereduced in vacuo and the residue was purified by column chromatography,eluting with 80% EtOAc/Hexane) to give an impure product, which wastriturated with pentane, followed by trituration with 4:1 pentane:Et₂Oto give the desired compound (50 mg).

LCMS: m/z 384.25 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.12-1.40 (m, 4H) 1.57-1.72 (m, 2H)1.82-2.10 (m, 2H) 3.39-3.49 (m, 1H) 3.67-3.79 (m, 1H) 4.80 (d, J=5.2 Hz,1H) 5.54 (s, 2H) 7.27 (dd, J=8.4, 4.8 Hz, 1H) 7.31 (d, J=8.4 Hz, 2H)7.40 (dd, J=6.4, 2.0 Hz, 2H) 8.05 (dd, J=8.4, 1.2 Hz, 1H) 8.41 (s, 1H)8.49 (dd, J=4.4, 1.2 Hz, 1H) 8.74 (d, J=8.0 Hz, 1H).

Example 24:1-(2,4-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of palladium (II) acetate (2 mg) in toluene (3 mL) was purgedunder nitrogen. To this mixture was added XantPhos (7 mg), followed byNa₂CO₃ (198 mg) and (1S,2S)-2-aminocyclohexanol (107 mg).1-(2,4-difluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made byalkylation of Intermediate 1, using a method analogous to that describedin Intermediate 18), (0.23 g) was then added and the reaction was purgedwith CO gas and stirred under CO at 85° C. overnight, at which point TLCindicated disappearance of SM. The reaction was cooled to rt, dilutedwith water and extracted 2× with EtOAc. Combined organic layers werereduced in vacuo and the residue was purified by column chromatography,eluting with 80% EtOAc/Hexane) to give the desired compound (80 mg).

LCMS: m/z 386.17 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.27-1.85 (m, 6H) 2.08-2.19 (m, 2H)3.53-3.65 (m, 1H) 3.85-3.97 (m, 1H) 4.51 (br. S., 1H) 5.37 (s, 2H)6.82-6.97 (m, 2H) 7.07 (dd, J=14.4, 8.4 Hz, 1H) 7.24 (dd, J=8.4, 4.8 Hz,1H) 7.75 (d, J=8.8 Hz, 1H) 8.17 (br. s., 1H) 8.53 (dd, J=4.8, 1.2 Hz,1H) 9.05 (d, J=6.4 Hz, 1H)

Example 25:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of palladium (II) acetate (4.0 mg) in toluene (3 mL) wasadded XantPhos (10.0 mg) followed by Na₂CO₃ (273 mg),(1S,2S)-2-aminocyclohexanol (196 mg) and3-iodo-1-((6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine (madeby alkylation of Intermediate 1, using a method analogous to thatdescribed in Intermediate 18), (300 mg) was purged with Argon and thenwith CO gas for 5 min. The mixture was then stirred under CO at 85° C.overnight, at which point TLC indicated formation of product. Thereaction was cooled to rt and reduced in vacuo. The residue was purifiedby column chromatography, eluting with 57% EtOAc/Hexane) to give animpure product, which was purified by preparative HPLC to give thedesired product (50 mg).

LCMS: m/z 365.08 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.29 (d, J=8.2 Hz, 4H) 1.62 (d, J=11.3 Hz,2H) 1.86 (br. s., 1H) 2.01 (d, J=9.8 Hz, 1H) 2.40 (s, 3H) 3.36-3.43 (m,1H) 3.70 (br. s., 1H) 4.79 (d, J=5.2 Hz, 1H) 5.51 (s, 2H) 7.19 (d, J=7.9Hz, 1H) 7.27 (dd, J=8.4, 4.7 Hz, 1H) 7.57 (dd, J=7.9, 2.4 Hz, 1H) 8.12(dd, J=8.6, 1.2 Hz, 1H) 8.42 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 8.52 (s, 1H)8.73 (d, J=7.9 Hz, 1H).

Example 26:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of Palladium (II) acetate (5.0 mg) in toluene (4 mL) wasadded XantPhos (12.0 mg) followed by Na₂CO₃ (337 mg),(1S,2S)-2-aminocyclohexanol (241 mg) and3-iodo-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine (madeby alkylation of Intermediate 1, using a method analogous to thatdescribed in Intermediate 18), (370 mg) was purged with Argon and thenwith CO gas for 5 min. The mixture was then stirred under CO at 85° C.overnight, at which point TLC indicated formation of product. Thereaction was cooled to rt and reduced in vacuo. The residue was purifiedby column chromatography, eluting with 60% EtOAc/Hexane) to give animpure product, which was purified by preparative HPLC to give thedesired product (25 mg).

LCMS: m/z 365.08 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.29 (d, J=8.2 Hz, 4H) 1.65 (s, 2H) 1.87(br. s., 1H) 2.03 (d, J=10.4 Hz, 1H) 2.23 (s, 3H) 3.40 (d, J=4.9 Hz, 1H)3.72 (d, J=7.9 Hz, 1H) 4.80 (d, J=5.2 Hz, 1H) 5.57 (s, 2H) 7.16 (d,J=7.9 Hz, 1H) 7.24 (dd, J=8.4, 4.7 Hz, 1H) 7.57 (dd, J=7.8, 2.0 Hz, 1H)8.00 (dd, J=8.4, 1.4 Hz, 1H) 8.33 (s, 2H) 8.47 (dd, J=4.7, 1.4 Hz, 1H)8.74 (d, J=7.6 Hz, 1H)

Example 27:1-(4-Fluorobenzyl)-N-(trans-2-hydroxycyclopentyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid(Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogenwas added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stirfor 15 minutes and then trans-2-aminocyclopentanol hydrochloride (56.0mg) was introduced. The reaction was left to stir overnight at roomtemperature, at which point LC-MS indicated completion. The reactionmixture was transferred to a seperating flask and EtOAc and water wereadded. The phases were separated and the aqueous phase was extractedtwice more with ethyl acetate. The organic phases were combined, washedwith brine and the solvent was removed in vacuo. The residue waspurified by column chromatography (normal phase, 25 g, Biotage SNAPcartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane,followed by 0-15% MeOH/EtOAc) to give the desired product as a racemicmixture of trans isomers (65 mg).

LCMS: m/z 354.57 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.64-1.91 (m, 4H) 1.97-2.15 (m, 1H)2.17-2.35 (m, 1H) 4.05-4.22 (m, 2H) 5.29 (s, 2H) 6.93-7.22 (m, 5H) 7.59(d, J=8.3 Hz, 1H) 8.09 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 9.11 (d, J=3.1 Hz,1H)

Example 28:1-(4-Fluorobenzyl)-N-(trans-2-hydroxycycloheptyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid(Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogenwas added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stirfor 15 minutes and then trans-2-aminocycloheptanol (52.6 mg) wasintroduced. The reaction was left to stir overnight at room temperature,at which point LC-MS indicated completion. The reaction mixture wastransferred to a seperating flask and EtOAc and water were added. Thephases were separated and the aqueous phase was extracted twice morewith EtOAc. The organic phases were combined and washed with brine.Solvent was removed in vacuo. The residue was purified by columnchromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mLper min, gradient 0% to 100% EtOAc in hexane, followed by 0-15%MeOH/EtOAc) to give the desired product as a racemic mixture of transisomers (77 mg).

LCMS: m/z 382.60 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.41-2.02 (m, 10H) 3.77-3.92 (m, 1H) 4.07(qd, J=7.4, 3.6 Hz, 1H) 5.22-5.36 (m, 2H) 6.94-7.21 (m, 5H) 7.60 (d,J=8.3 Hz, 1H) 8.06 (s, 1H) 8.50 (d, J=4.7 Hz, 1H) 9.18 (d, J=6.1 Hz,1H).

Example 29:1-(4-Fluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid(Intermediate 20), (119 mg) in DMF (2.3 mL) stirred at rt under nitrogenwas added HATU (268 mg) and TEA (0.12 mL). This mixture was left to stirfor 15 minutes and then tetrahydro-2H-pyran-4-amine (40 mg) wasintroduced. The reaction was left to stir overnight at room temperature,at which point LC-MS indicated completion. The reaction mixture wastransferred to a seperating flask and EtOAc and water were added. Thephases were separated and the aqueous phase was extracted twice morewith EtOAc. The organic phases were combined, washed with brine and thesolvent was removed in vacuo. The residue was purified by columnchromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mLper min, gradient 0% to 100% EtOAc in hexane, followed by 0-15%MeOH/EtOAc) to give impure product, which was purified a second time bycolumn chromatography (normal phase, 25 g, Biotage SNAP cartridgeKP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by0-15% MeOH/EtOAc) to give the desired product (5 mg).

LCMS: m/z 354.46 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.67-1.84 (m, 2H) 2.07 (d, J=11.3 Hz, 2H)3.62 (t, J=10.4 Hz, 2H) 3.98-4.09 (m, 2H) 4.23-4.39 (m, 1H) 5.32 (s, 2H)6.96-7.09 (m, 2H) 7.09-7.22 (m, 3H) 7.60 (d, J=8.3 Hz, 1H) 8.09 (s, 1H)8.52 (d, J=4.7 Hz, 1H) 8.98 (d, J=7.3 Hz, 1H).

Example 30:1-(4-Fluorobenzyl)-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of crude tert-butyl4-(1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylate(Intermediate 21), (184 mg) in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt under nitrogenovernight, at which point LC-MS indicated disappearance of SM. Thereaction was then reduced in vacuo and taken up into MeOH (1 mL) andloaded onto a 2 g SCX-2 cartridge, washing with 20 ml MeOH, followed by20 ml 2M NH3/MeOH. The ammonia-containing fraction were collected andreduced in vacuo to yield the desired product (43 mg)

LCMS: m/z 353.58 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.53-1.71 (m, 2H) 2.03-2.16 (m, 2H) 2.43(br. s., 1H) 2.75-2.89 (m, 2H) 3.12-3.24 (m, 2H) 4.13-4.30 (m, 1H) 5.31(s, 2H) 6.96-7.06 (m, 2H) 7.08-7.21 (m, 3H) 7.58 (d, J=8.2 Hz, 1H) 8.07(s, 1H) 8.50 (d, J=4.7 Hz, 1H) 8.97 (d, J=7.7 Hz, 1H)

Example 31:1-(4-Fluorobenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a stirred suspension of1-(4-fluorobenzyl)-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Example 30), (53 mg) in DCM (1.2 mL) at rt was added TEA (0.028 mL) andformaldehyde (0.023 mL) followed by sodium tri-acetoxyborohydride (115mg). The resultant reaction mixture was stirred at rt overnight, atwhich point LC-MS showed product formation. The reaction mixture wasdiluted with DCM and was washed with saturated NaHCO₃. The aqueous layerwas re-extracted with DCM and the combined organic layers were furtherwashed with saturated NaHCO₃, dried over Na₂SO₄, filtered andconcentrated to dryness to give the desired product (37 mg)

LCMS: m/z 367.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.68-1.84 (m, 2H) 2.01-2.15 (m, 2H)2.18-2.38 (m, 5H) 2.82 (d, J=11.4 Hz, 2H) 4.04-4.19 (m, 1H) 5.30 (s, 2H)6.95-7.07 (m, 2H) 7.06-7.19 (m, 3H) 7.58 (d, J=8.3 Hz, 1H) 8.06 (s, 1H)8.50 (d, J=4.7 Hz, 1H) 8.95 (d, J=7.0 Hz, 1H)

Example 32:7-Cyano-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of7-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 27), (300 mg), 1-(bromomethyl)-4-fluorobenzene (219 mg)and cesium carbonate (791 mg) was added DMF (5 mL) and left to stir atrt for 1 h. The crude product was purified by prep. LC-MS to give thedesired compound (57 mg).

LCMS: m/z 393.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.01-1.64 (m, 4H) 1.80 (d, J=11.0 Hz, 2H)1.93-2.36 (m, 2H) 3.54 (td, J=9.9, 4.3 Hz, 1H) 3.73-4.21 (m, 2H)5.59-5.77 (m, 2H) 7.06 (t, J=8.5 Hz, 2H) 7.19 (dd, J=8.3, 5.3 Hz, 2H)7.45 (d, J=4.8 Hz, 1H) 8.20 (s, 1H) 8.61 (d, J=4.9 Hz, 1H) 8.76 (d,J=6.4 Hz, 1H)

Example 33:7-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of7-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 27), (170 mg), cesium carbonate (448 mg), DMF (3 mL) wasadded 1-(chloromethyl)-4-(trifluoromethyl)benzene (128 mg). Afterstirring overnight the solid was filtered and the product purified byprep. LCMS to give the pure desired compound (92 mg).

LCMS: m/z 393.64 [M+H]⁺.

¹H NMR (600 MHz, DMSO-d₆): ppm 1.21-1.37 (m, 4H) 1.63 (br. s., 1H) 1.69(br. s., 1H) 1.90 (br. s., 1H) 2.08 (br. s., 1H) 3.37-3.51 (m, 1H)3.70-3.80 (m, 1H) 4.79 (d, J=5.6 Hz, 1H) 5.92 (s, 2H) 7.29 (d, J=7.9 Hz,2H) 7.73 (d, J=8.2 Hz, 2H) 7.77 (d, J=5.0 Hz, 1H) 8.60 (d, J=7.6 Hz, 1H)8.66 (s, 1H) 8.71 (d, J=4.7 Hz, 1H)

Example 34 and 35:N-(trans-4,4-Difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of 1-(4-fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 18), (150 mg), trans-2-amino-5,5-difluorocyclohexanol(Intermediate 33), (97 mg) palladium (II) acetate (2.9 mg), XantPhos(14.8 mg) and TEA (0.119 mL) in toluene (5 mL) was sealed in a reactionvial. This was purged with carbon monoxide and heated to 80° C.overnight. The reaction mixture was filtered through a pad of celitewashing with EtOAc. The filtrate was evaporated and purified bychromatography (normal phase, Biotage SNAP cartridge KP-Sil, gradient20% to 100% EtOAc in n-hexane, 10% Methanol in EtOAc). Chiralchromatographic separation (×4) using preparative IE column (i.d. 20 mm;length 250 mm) and 95% DCM, 5% EtOH (v/v) as eluent, injection volume:1500 microL, flow rate: 18.0 mL/min, oven temperature: 30 C, affordedthe first major eluting peak (retention time: 7.42 min)N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamideenantiomer 1, a single enantiomer of trans relative stereochemistry butunknown absolute configuration, (Example 34) (82 mg).

LCMS: m/z 404.56 [M+H]⁺.

¹H NMR (600 MHz, DMSO-d₆) ppm 1.39-1.49 (m, 1H) 1.89-2.15 (m, 4H)2.27-2.36 (m, 1H) 3.60-3.68 (m, 1H) 3.86-3.92 (m, 1H) 5.22 (d, J=5.6 Hz,1H) 5.52 (s, 2H) 7.13-7.19 (m, 2H) 7.27 (dd, J=8.2, 4.7 Hz, 1H)7.34-7.40 (m, 2H) 8.08 (dd, J=8.4, 1.3 Hz, 1H) 8.41 (s, 1H) 8.49 (dd,J=4.7, 1.2 Hz, 1H) 8.74 (d, J=7.3 Hz, 1H) The second minor eluting peak(retention time: 10.86 min) affordedN-(trans-4,4-difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamideenantiomer 2, a single enantiomer of trans relative stereochemistry butunknown absolute configuration, (Example 35) (27 mg).

LCMS: m/z 404.19 [M+H]⁺.

¹H NMR (600 MHz, DMSO-d₆) ppm 1.39-1.49 (m, 1H) 1.89-2.15 (m, 4H)2.27-2.36 (m, 1H) 3.60-3.68 (m, 1H) 3.86-3.92 (m, 1H) 5.22 (d, J=5.6 Hz,1H) 5.52 (s, 2H) 7.13-7.19 (m, 2H) 7.27 (dd, J=8.2, 4.7 Hz, 1H)7.34-7.40 (m, 2H) 8.08 (dd, J=8.4, 1.3 Hz, 1H) 8.41 (s, 1H) 8.49 (dd,J=4.7, 1.2 Hz, 1H) 8.74 (d, J=7.3 Hz, 1H)

Example 36:N-(cis-4,4-Difluoro-2-hydroxycyclohexyl)-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of 1-(4-fluorobenzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 18), (100 mg), cis-2-amino-5,5-difluorocyclohexanol(Intermediate 37), (64.4 mg), palladium (II) acetate (1.9 mg), XantPhos(9.9 mg), TEA (0.08 mL) and toluene (2 mL) was sealed in a reactionvial. This was then exposed to an atmosphere of carbon monoxide andheated to 80° C. After two hours additionalcis-2-amino-5,5-difluorocyclohexanol (42.6 mg), palladium (II) acetate(1.9 mg), XantPhos (9.9 mg) and TEA (0.04 mL) were added. Heating wascontinued at 80° C. under an atmosphere of carbon monoxide for 18 hours.The reaction mixture was cooled to room temperature, diluted with EtOAc,filtered through a pad of celite and evaporated under vacuum. Theresidue was purified by column chromatography (reverse phase, gradient5% to 95% MeCN in water, 0.1% acetic acid buffer in both solvents). Thedesired fractions were combined, concentrated under vacuum to 50%volume, diluted with saturated sodium bicarbonate solution and extractedinto EtOAc (2×). The combined organic extracts were washed with brine(1×), dried (Na₂SO₄), filtered and evaporated under vacuum to give thedesired compound, a single enantiomer of cis relative stereochemistrybut unknown absolute configuration (36.8 mg).

LCMS: m/z 404.56 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.62-1.75 (m, 1H) 1.91-2.05 (m, 3H)2.05-2.34 (m, 2H) 3.96 (br. s., 1H) 4.19 (br. s., 1H) 5.24 (d, J=3.9 Hz,1H) 5.51 (s, 2H) 7.13-7.20 (m, 2H) 7.26 (dd, J=8.3, 4.7 Hz, 1H) 7.37(dd, J=8.4, 5.5 Hz, 2H) 8.08 (d, J=8.3 Hz, 1H) 8.41 (s, 1H) 8.48 (d,J=5.1 Hz, 1H) 8.98 (d, J=7.8 Hz, 1H)

Example 37:1-(4-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 45), (140 mg), 1-(bromomethyl)-4-fluorobenzene (91 mg) andcesium carbonate (363 mg) was added DMF (3 mL) and left to stir at rtfor 22 h. The crude product was purified by prep. LC-MS to give thedesired compound (113 mg).

LCMS: m/z 398.64 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.89-1.92 (m, 6H) 1.97-2.17 (m, 2H) 3.56(br. s., 1H) 3.77-3.92 (m, 1H) 3.97 (s, 3H) 4.20-4.89 (br. s., 1H) 5.53(s, 2H) 6.66 (d, J=5.4 Hz, 1H) 6.87-7.06 (m, 2H) 7.07-7.18 (m, 2H) 7.94(br. s., 1H) 8.35 (d, J=5.4 Hz, 1H) 9.15 (d, J=5.9 Hz, 1H)

¹⁹F NMR (377 MHz, CDCl₃) ppm −114.10 (br. s.)

Example 38:1-(4-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 49), (130 mg), 1-(bromomethyl)-4-fluorobenzene (93 mg) andcesium carbonate (337 mg) in DMF (3 mL) were stirred at rt for 3 days.The solid was filtered and the product purified by prep. LCMS to givethe desired compound (107 mg).

LCMS: m/z 398.59 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.23-1.54 (m, 4H) 1.79 (d, J=9.2 Hz, 2H)2.16 (br. s., 2H) 3.54 (td, J=9.9, 4.4 Hz, 1H) 3.65 (br. S., 1H)3.80-3.92 (m, 1H) 4.01 (s, 3H) 5.29 (s, 2H) 6.66 (d, J=8.8 Hz, 1H)6.96-7.09 (m, 2H) 7.09-7.17 (m, 2H) 7.51 (d, J=8.9 Hz, 1H) 8.10 (s, 1H)9.00 (br. s., 1H)

Example 39:5-Chloro-1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of5-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 53), (120 mg), 1-(bromomethyl)-4-fluorobenzene (85 mg) andcesium carbonate (306 mg) in DMF (3 mL) was stirred at rt overnight. Theunwanted solid was filtered and the filtrate purified by prep. LCMS togive the desired product (90 mg).

LCMS: m/z 402.53 [M+H]⁺.

¹H NMR (600 MHz, CDCl₃) ppm 1.24-1.62 (m, 4H) 1.77-1.87 (m, 2H)2.13-2.20 (m, 2H) 3.60 (td, J=10.0, 4.4 Hz, 1H) 3.87-3.98 (m, 1H) 5.33(s, 2H) 7.04-7.09 (m, 2H) 7.13-7.21 (m, 3H) 7.57 (d, J=8.8 Hz, 1H) 8.25(br. s., 1H) 8.73 (br. s., 1H)

Example 40:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

1-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-5-methyl-1H-pyrrolo[3,2-b]pyridine(Intermediate 58) (150 mg), palladium (II) acetate (2.8 mg), XantPhos(14.2 mg), trans-(1S,2S)-2-aminocyclohexanol hydrochloride (93 mg),toluene (2.6 mL) and TEA (0.17 mL) were placed in a microwave tube witha CO balloon. The microwave tube was purged with CO then heated to 80°C. overnight to give a dark reaction mixture with a solid precipitate.Palladium (II) acetate (2.8 mg) and XantPhos (14.2 mg) were added andthe reaction was stirred overnight at 80° C. under CO. The solvent wastransferred to a round bottom flask then the solid remaining in themicrowave tube was dissolved in THF (˜1 mL) with sonication andtransferred to the round bottom flask and the solvents evaporated. Tothe resulting solid was added DMF (3 mL) and the suspension sonicatedand filtered to remove the small amount of insoluble solid remaining.Preparative LCMS followed by column chromatography (normal phase, 10 gsilica, Biotage SNAP cartridge KP-Sil, gradient 0% to 10% EtOAc inn-hexane) gave the desired compound (90 mg).

LCMS: m/z 430.65 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.21-1.62 (m, 4H) 1.79 (d, J=9.5 Hz, 2H)2.07-2.24 (m, 2H) 2.72 (br. s., 3H) 3.65 (br. s., 1H) 3.79-3.94 (m, 1H)5.33-5.45 (m, 2H) 6.48 (t, J=2.1 Hz, 1H) 7.07 (d, J=7.8 Hz, 1H)7.18-7.33 (m, 2H) 7.65-7.77 (m, 2H) 7.90 (d, J=2.1 Hz, 1H) 9.32 (br. s.,1H)

Example 41:1-(4-(1H-Pyrazol-1-yl)benzyl)-5-cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

5-Cyano-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 63), (120 mg), 1-(4-(bromomethyl)phenyl)-1H-pyrazole (110mg) and cesium carbonate (316 mg) in DMF (3 mL) were stirred at rt for7.5 h. The solid was filtered and the product purified by preparativeLCMS to give the desired compound (62 mg).

LCMS: m/z 441.57 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.61 (m, 4H) 1.70-1.86 (m, 2H) 2.13 (d,J=11.5 Hz, 2H) 3.55 (td, J=9.7, 4.3 Hz, 1H) 3.82-3.96 (m, 1H) 5.43 (s,2H) 6.48 (s, 1H) 7.26-7.32 (m, 2H) 7.57 (d, J=8.4 Hz, 1H) 7.66-7.76 (m,4H) 7.91 (d, J=2.5 Hz, 1H) 8.38 (s, 1H)

Example 42:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

In a microwave vial, a mixture of of1-(4-bromobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Example 56), (200 mg), 1-methyl-2-(tributylstannyl)-1H-imidazole(Inorg. Chem. 2008, 47, 990-998), (520 mg) in 1,4-dioxane (1.3 mL) waspurged with nitrogen. Pd(PPh₃)₄ (54.0 mg) was added, the mixture wasdegassed further before the vial was sealed and heated to 140° C. in themicorwave for 2 h. Saturated aqueous sodium bicarbonate solution wasadded and the crude product was extracted with EtOAc (3×). The organicphases were combined, washed with brine, dried (MgSO₄), filtered andevaporated under vacuum. The residue was purified by columnchromatography (normal phase, 11 g, Biotage SNAP cartridge KP-NH, 14 mLper min, gradient 0% to 100% EtOAc in n-hexane, followed by 0-10% MeOHin EtOAc). The product was further purified by preparatory LC-MS toafford the title compound (94 mg).

LCMS: m/z 430.66, [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.20-1.45 (m, 3H), 1.45-1.60 (m, 1H), 1.76(br. s., 2H), 2.11 (d, J=12.5 Hz, 2H), 3.54 (td, J=9.9, 4.6 Hz, 1H),3.69 (s, 3H), 3.79-3.96 (m, 1H), 5.34 (s, 2H), 6.94 (s, 1H), 7.08 (d,J=0.7 Hz, 1H), 7.13 (dd, J=8.3, 4.8 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H),7.57 (d, J=8.2 Hz, 2H), 7.60 (d, J=0.9 Hz, 1H), 8.08 (s, 1H), 8.36-8.56(m, 1H), 9.03 (d, J=6.6 Hz, 1H)

Example 43:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

In a microwave vial, a mixture of of1-(4-bromobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Example 56), (300 mg), 1-methyl-4-(tributylstannyl)-1H-imidazole (364mg) in 1,4-dioxane (1.8 mL) was purged with nitrogen. Pd(PPh₃)₄ (81.0mg) was added, the mixture was degassed further before the vial wassealed and heated to 140° C. in the microwave for 1 h. Saturated aqueoussodium bicarbonate solution was added and the crude product wasextracted with EtOAc (3×). The organic phases were combined, washed withbrine, dried (MgSO₄), filtered and evaporated under vacuum. The residuewas purified by column chromatography (normal phase, 28 g, Biotage SNAPcartridge KP-NH, 25 mL per min, gradient 0% to 100% EtOAc in n-hexane,followed by 0-20% MeOH in EtOAc). The product was further purified bysolid phase extraction (SCX-2 g cartridge), eluting components firstwith methanol, followed by eluting product with 2 M methanolic ammonia.The product was further purified by preparatory LC-MS to give the titlecompound (159 mg).

LCMS: m/z 430.64, [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.14-1.45 (m, 3H), 1.45-1.60 (m, 1H), 1.75(d, J=3.1 Hz, 2H), 2.02-2.18 (m, 2H), 3.54 (td, J=9.8, 4.4 Hz, 1H), 3.66(s, 3H), 3.79-3.96 (m, 1H), 5.26 (s, 2H), 6.98-7.20 (m, 4H), 7.42 (s,1H), 7.57 (d, J=8.3 Hz, 1H), 7.67 (d, J=7.9 Hz, 2H), 8.05 (s, 1H), 8.44(d, J=4.6 Hz, 1H), 9.02 (d, J=6.6 Hz, 1H)

Example 44:1-(2-Fluoro-4-(6-methylpyridin-2-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

Into a sealable tube, was added sodium carbonate (277 mg), XantPhos (15mg), Pd(OAc)₂ (5.8 mg) and toluene (10 mL). The reaction mixture waspurged with nitrogen before adding (1S,2S)-2-aminocyclohexanol (225 mg),and purged again before the addition of1-(2-fluoro-4-(6-methylpyridin-2-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 66), (580 mg). The reaction mixture was purged furtherwith nitrogen, then purged with carbon monoxide, before heating thereaction mixture at 70° C. overnight. Once cooled, the reaction mixturewas evaporated under vacuum and the crude product was purified by columnchromatography, eluting with 2:98 MeOH:CH₂Cl₂ to afford the productwhich was further purified by preparatory HPLC to yield the titlecompound (0.06 g).

LCMS: m/z 459.31 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) ppm 1.16-1.36 (m, 4H) 1.53-1.72 (m, 2H) 1.87(br. s., 1H) 2.03 (d, J=11.0 Hz, 1H), 2.51 (s, 3H) 3.42 (br. s., 1H)3.72 (d, J=8.2 Hz, 1H) 4.80 (d, J=4.3 Hz, 1H) 5.66 (s, 2H) 7.19-7.38 (m,3H) 7.76 (d, J=4.3 Hz, 2H) 7.82-7.95 (m, 2H) 8.08 (d, J=8.2 Hz, 1H) 8.33(s, 1H) 8.50 (d, J=4.6 Hz, 1H) 8.75 (d, J=7.6 Hz, 1H)

Example 45:1-(2-Fluoro-4-(2-methylpyridin-4-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

Into a sealable tube, was added sodium carbonate (220 mg), XantPhos (12mg), Pd(OAc)₂ (4.8 mg) and toluene (8 mL). The reaction mixture waspurged with nitrogen before adding (1S,2S)-2-aminocyclohexanol (186 mg),and purged again before the addition1-(2-fluoro-4-(2-methylpyridin-4-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 69), (480 mg). The reaction mixture was purged furtherwith nitrogen, then purged with carbon monoxide, before heating thereaction mixture at 70° C. overnight. Once cooled, the reaction mixturewas evaporated under vacuum and the crude product was purified by columnchromatography, eluting with 2:98 MeOH:CH₂Cl₂ to afford the titlecompound (100 mg).

LCMS: m/z 459.31 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.17-1.70 (m, 4H) 1.79 (br. s., 2H) 2.13 (d,J=11.3 Hz, 2H) 2.63 (s, 3H) 3.45-3.63 (m, 1H) 3.80-4.01 (m, 1H) 4.48(br. s., 1H) 5.43 (s, 2H) 7.13 (t, J=7.8 Hz, 1H) 7.19-7.26 (m, 2H)7.30-7.41 (m, 3H) 7.75 (d, J=8.2 Hz, 1H) 8.14 (s, 1H) 8.54 (dd, J=15.9,4.9 Hz, 2H) 9.05 (d, J=6.7 Hz, 1H)

Example 46:1-((4′-Fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(trans-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of Pd(OAc)₂ (3 mg) in toluene (3 mL) was purged with nitrogen.To which, was sequentially added XantPhos (8 mg), sodium carbonate (220mg), trans-2-aminocyclohexanol (120 mg) and1-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(Intermediate 72), (300 mg). The reaction mixture was purged with carbonmonoxide gas for 10 min before heating the reaction at 85° C. overnight.Once cooled, the reaction mixture was evaporated under vacuum and theresidue purified by column chromatography (silica), eluting with 20:80EtOAc/hexanes to afford the title compound as a racemic mixture of transisomers (50 mg).

LCMS: m/z 444.44 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) ppm 1.16-1.41 (m, 4H) 1.61 (br. s., 2H) 1.87(br. s., 1H) 1.97-2.10 (m, 1H) 3.27-3.47 (m, 1H) 3.72 (d, J=8.5 Hz, 1H)4.80 (br. S., 1H) 5.57 (s, 2H) 7.21-7.32 (m, 3H) 7.37 (d, J=8.2 Hz, 2H)7.60 (d, J=8.2 Hz, 2H) 7.65 (dd, J=8.7, 5.6 Hz, 2H) 8.12 (d, J=8.2 Hz,1H) 8.43 (s, 1H) 8.49 (d, J=4.9 Hz, 1H) 8.74 (d, J=7.6 Hz, 1H)

Example 47:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (145 mg), potassium hydroxide (72.2 mg) and potassiumiodide (121 mg) in THF (2 mL) and water (2 mL) was added1-(4-(bromomethyl)phenyl)-1H-pyrazole (172 mg) and the resultingsolution stirred at 75° C. for 1 h 40 min. The reaction mixture wascooled, brine added and extracted with EtOAc (3×), the combined organicextracts dried (MgSO₄), filtered and evaporated under vacuum.Preparative LCMS of the residue gave the desired compound (50 mg).

LCMS: m/z 416.67 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.64 (m, 4H) 1.79 (dd, J=6.5, 2.3 Hz,2H) 2.10-2.20 (m, 2H) 3.59 (td, J=9.9, 4.4 Hz, 1H) 3.84-3.98 (m, 1H)5.39 (s, 2H) 6.48 (t, J=2.1 Hz, 1H) 7.14-7.30 (m, 3H) 7.59-7.75 (m, 4H)7.90 (d, J=2.6 Hz, 1H) 8.19 (br. s., 1H) 8.49-8.55 (m, 1H) 9.06 (d,J=6.6 Hz, 1H)

Example 48:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1R,2R)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 73, (133 mg), KOH (66 mg) and KI (111 mg) in THF (1.75 mL)and water (1.75 mL) was added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (158mg) and the resulting solution stirred at 75° C. overnight. The solutionwas allowed to cool to rt before adding brine, and then extracted withEtOAc (3×). The organic extracts were combined and then dried (MgSO₄),filtered and evaporated under vacuum. The residue was purified by prep.LC-MS to give the desired compound (81 mg).

LCMS: m/z 416.63 [M+H]⁺.

¹H NMR (600 MHz, CDCl₃) ppm 1.25-1.51 (m, 3H) 1.57 (qd, J=12.4, 3.7 Hz,1H) 1.76-1.86 (m, 2H) 2.16 (d, J=12.0 Hz, 2H) 3.60 (td, J=10.0, 4.4 Hz,1H) 3.88-3.97 (m, 1H) 5.40 (s, 2H) 6.49 (t, J=2.1 Hz, 1H) 7.19 (dd,J=8.2, 4.7 Hz, 1H) 7.26 (d, J=8.5 Hz, 2H) 7.64 (d, J=8.2 Hz, 1H) 7.69(d, J=8.5 Hz, 2H) 7.74 (d, J=1.5 Hz, 1H) 7.92 (d, J=2.4 Hz, 1H) 8.18(br. s., 1H) 8.48-8.57 (m, 1H) 9.06 (d, J=6.8 Hz, 1H)

Example 49:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of1-(4-(1H-pyrazol-1-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made byalkylation of Intermediate 1, using a method analogous to that describedin Intermediate 18), (300 mg), palladium (II) acetate (3.0 mg), XantPhos(8 mg), tetrahydro-2H-pyran-3-amine (113 mg), sodium carbonate (230 mg)and toluene (3 mL) were purged with CO then heated to 80° C. overnight.The solvent was evaporated and the residue was purified twice by columnchromatography (normal phase, 10 g silica, Biotage SNAP cartridgeKP-Sil, gradient 2% methanol in EtOAc then 1% methanol in EtOAc) to givethe desired compound as a racemate (50 mg).

LCMS: m/z 402.19 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): ppm 1.51-1.81 (m, 3H) 1.96 (br. s., 1H) 3.39(d, J=7.0 Hz, 1H) 3.51-3.60 (m, 1H) 3.61-3.70 (m, 1H) 3.81 (dd, J=10.8,2.9 Hz, 1H) 4.02 (dd, J=7.6, 3.7 Hz, 1H) 5.57 (s, 2H) 6.53 (dd, J=2.4,1.8 Hz, 1H) 7.29 (dd, J=8.2, 4.6 Hz, 1H) 7.45 (d, J=8.9 Hz, 2H) 7.72 (d,J=1.8 Hz, 1H) 7.77-7.84 (m, 2H) 8.07-8.15 (m, 1H) 8.42-8.48 (m, 2H) 8.51(dd, J=4.7, 1.4 Hz, 1H) 8.86 (d, J=8.2 Hz, 1H)

Example 50:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-cyclohexyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture of1-(4-(1H-pyrazol-1-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made byalkylation of Intermediate 1, using a method analogous to that describedin Intermediate 18), (200 mg), palladium (II) acetate (2.0 mg), XantPhos(5 mg), cyclohexylamine (74 mg), sodium carbonate (160 mg) and toluene(2 mL) were purged with CO then heated to 85° C. overnight. The reactionmixture was diluted with EtOAc, washed with water and the aqueous phaseextracted with EtOAc. The combined organic extracts were dried (MgSO₄),filtered and evaporated under vacuum and the residue purified by columnchromatography (normal phase, gradient 0% to 40% EtOAc in n-hexane)followed by prep. LCMS to give the pure desired compound (55 mg).

LCMS: m/z 400.40 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.21-1.47 (m, 5H) 1.56 (br. s., 1H) 1.70(br. s., 2H) 1.90 (d, J=9.8 Hz, 2H) 3.89 (d, J=8.2 Hz, 1H) 5.56 (s, 2H)6.49-6.56 (m, 1H) 7.28 (dd, J=8.4, 4.7 Hz, 1H) 7.45 (d, J=8.9 Hz, 2H)7.72 (d, J=1.5 Hz, 1H) 7.80 (d, J=8.6 Hz, 2H) 8.10 (dd, J=8.2, 1.2 Hz,1H) 8.44 (s, 1H) 8.45-8.47 (m, 1H) 8.50 (dd, J=4.7, 1.4 Hz, 1H) 8.73 (d,J=8.2 Hz, 1H)

Example 51:1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of1-(4-(1H-pyrazol-1-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (made byalkylation of Intermediate 1, using a method analogous to that describedin Intermediate 18), (200 mg), palladium (II) acetate (3 mg), XantPhos(6 mg), 4,4-difluorocyclohexanamine hydrochloride (129 mg), sodiumcarbonate (159 mg) and toluene (2 mL) was purged with CO then heated to85° C. overnight. The reaction mixture was diluted with EtOAc, washedwith water and the aqueous phase extracted with EtOAc. The combinedorganic extracts were dried (MgSO₄), filtered and evaporated undervacuum and the residue was purified by column chromatography (normalphase, gradient 0% to 50% EtOAc in n-hexane) followed by prep. LCMS togive the pure desired compound (50 mg).

LCMS: m/z 436.36 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.61 (br. s., 2H) 1.96-2.12 (m, 6H) 4.09(br. s., 1H) 5.57 (s, 2H) 6.50-6.56 (m, 1H) 7.29 (dd, J=8.6 4.6 Hz, 1H)7.45 (d, J=8.6 Hz, 2H) 7.73 (d, J=1.5 Hz, 1H) 7.80 (d, J=8.6 Hz, 2H)8.12 (d, J=8.2 Hz, 1H) 8.41-8.55 (m, 3H) 8.80 (d, J=7.6 Hz, 1H)

Example 52:(S)-1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of (S)-tert-butyl3-(1-(4-(1H-pyrazol-1-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylate¹(300 mg) in 1,4-dioxane (6 mL) stirred at 0° C. was added HCl (4M in1,4-dioxane, 3 mL). The reaction mixture was allowed to warm to rtstirred for 3 hours at which point TLC indicated completion. Thereaction mixture was concentrated in vacuo and partitioned between CHCl₃and sat NaHCO₃. Layers were separated and the aqueous phase wasextracted with CHCl₃. Combined organic phases were reduced in vacuo. Theresidue was purified by flash chromatography, eluting with 2% MeOH/DCM)to give an impure product, which was triturated with diethyl ether,followed by pentane to give the desired product (185 mg).¹(S)-tert-butyl3-(1-(4-(1H-pyrazol-1-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylatewas prepared using a method analogous to that used for Example 18, by apalladium-catalysed aminocarbonylation of1-(4-(1H-pyrazol-1-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine,substituting (trans-2-aminocyclohexyl)methanol with (S)-tert-butyl3-aminopiperidine-1-carboxylate.1-(4-(1H-pyrazol-1-yl)benzyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine wasprepared using a method analogous to that used for Intermediate 18,alkylating Intermediate 1 with 1-(4-(bromomethyl)phenyl)-1H-pyrazole).

LCMS: m/z 401.10 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.34-1.56 (m, 2H) 1.65 (d, J=6.1 Hz, 1H)1.86 (br. s., 1H) 2.57 (br. s., 2H) 2.75 (d, J=13.1 Hz, 1H) 3.01 (d,J=11.9 Hz, 1H) 3.76-4.02 (m, 1H) 5.56 (s, 2H) 6.52 (dd, J=2.4, 1.8 Hz,1H) 7.27 (dd, J=8.2, 4.6 Hz, 1H) 7.44 (d, J=8.9 Hz, 2H) 7.71 (d, J=1.5Hz, 1H) 7.79 (d, J=8.6 Hz, 2H) 8.09 (dd, J=8.6, 1.2 Hz, 1H) 8.36-8.54(m, 3H) 8.78 (d, J=7.6 Hz, 1H)

Example 53:(R)-1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of (R)-tert-butyl3-(1-(4-(1H-pyrazol-1-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylate²(300 mg) in 1,4-dioxane (6 mL) stirred at 0° C. was added HCl (4M in1,4-dioxane, 3 mL). The reaction mixture was allowed to warm to rtstirred for 3 hours at which point TLC indicated completion. Thereaction mixture was concentrated in vacuo and triturated with diethylether. The residue was purified by flash chromatography, eluting with 2%MeOH/DCM) to give an impure product, which was triturated with EtOAc,followed by diethyl ether to give the desired product (180 mg).²(R)-tert-butyl3-(1-(4-(1H-pyrazol-1-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylatewas made using a method analogous to that used to prepare (S)-tert-butyl3-(1-(4-(1H-pyrazol-1-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)piperidine-1-carboxylatereferred to in Example 52.

LCMS: m/z 401.10 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.52 (br. s., 2H) 1.70 (br. s., 1H) 1.90(br. s., 1H) 2.50-2.63 (m, 2H) 2.82 (br. s., 1H) 3.09 (d, J=12.2 Hz, 1H)3.99 (br. s., 1H) 5.57 (s, 2H) 6.53 (dd, J=2.6, 1.7 Hz, 1H) 7.19-7.33(m, 1H) 7.45 (m, J=8.9 Hz, 2H) 7.73 (d, J=1.5 Hz, 1H) 7.80 (m, J=8.6 Hz,2H) 8.11 (dd, J=8.4, 1.4 Hz, 1H) 8.38-8.54 (m, 3H) 8.79 (d, J=7.9 Hz,1H).

Example 54:(S)-1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of(S)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,(Example 52), (130 mg), dichloroethane (3 mL) and formaldehyde (37%solution in water, 30 mg) was stirred at rt for 30 min before additionof sodium tri-acetoxyborohydride (270 mg). The reaction was stirred atrt for 3 hours, at which point, TLC indicated completion. The reactionwas diluted with sat. NaHCO₃ and extracted 2× with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and reduced in vacuo.The residue was purified by flash chromatography, eluting with 1%MeOH/DCM with 0.1% TEA added to give an impure product, which wastriturated with diethyl ether and EtOAc to give the desired product (57mg)

LCMS: m/z 415.11 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.41 (br. s., 1H) 1.57 (br. s., 1H) 1.75(d, J=17.1 Hz, 2H) 2.25 (br. s., 6H) 2.65-2.79 (m, 1H) 4.10 (br. s., 1H)5.56 (s, 2H) 6.43-6.55 (m, 1H) 7.27 (dd, J=8.4, 4.7 Hz, 1H) 7.44 (m,J=8.6 Hz, 2H) 7.71 (d, J=1.2 Hz, 1H) 7.79 (m, J=8.6 Hz, 2H) 8.10 (dd,J=8.2, 1.2 Hz, 1H) 8.40-8.51 (m, 3H) 8.81 (d, J=7.6 Hz, 1H)

Example 55:(R)-1-(4-(1H-Pyrazol-1-yl)benzyl)-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of(R)-1-(4-(1H-pyrazol-1-yl)benzyl)-N-(piperidin-3-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,(Example 53), (130 mg), dichloroethane (3 mL) and formaldehyde (37%solution in water, 30 mg) was stirred at rt for 30 min before additionof sodium tri-acetoxyborohydride (270 mg). The reaction was stirred atrt for 3 hours, at which point, TLC indicated completion. The reactionwas diluted with sat. NaHCO₃ and extracted 2× with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and reduced in vacuo.The residue was purified by flash chromatography, eluting with 2%MeOH/DCM with 0.1% TEA added to give an impure product, which wastriturated with diethyl ether and EtOAc to give the desired product (60mg)

LCMS: m/z 415.11 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.39 (br. s., 1H) 1.55 (br. s., 1H) 1.75(br. s., 2H) 2.20 (br. s., 6H) 2.77 (br. s., 1H) 4.08 (br. s., 1H) 5.56(s, 2H) 6.52 (dd, J=2.6, 1.7 Hz, 1H) 7.27 (dd, J=8.4, 4.7 Hz, 1H) 7.44(d, J=8.9 Hz, 2H) 7.71 (d, J=1.2 Hz, 1H) 7.79 (d, J=8.6 Hz, 2H) 8.10(dd, J=8.4, 1.4 Hz, 1H) 8.40-8.58 (m, 3H) 8.81 (d, J=6.4 Hz, 1H)

Example 56:1-(4-Bromobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4) (750 mg) and cesium carbonate (1.131 g) in DMF (10 mL)stirred at rt under nitrogen was added 1-bromo-4-(bromomethyl)benzene(795 mg) and the reaction mixture stirred for 2 h. The reaction was thendiluted with EtOAc, washed with water (3×), brine, dried (MgSO₄),filtered and evaporated under vacuum. The residue was purified by columnchromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mLper min, gradient 0% to 100% EtOAc in n-hexane, followed by 0-10% MeOHin EtOAc) to afford the title compound (900 mg).

LCMS: m/z 428.53 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.21-1.47 (m, 3H) 1.53 (qd, J=12.2, 3.2 Hz,1H) 1.77 (d, J=3.2 Hz, 2H) 2.11 (d, J=11.1 Hz, 2H) 3.55 (t, J=9.5 Hz,1H) 3.81-3.94 (m, 1H) 5.27 (s, 2H) 6.99 (d, J=8.2 Hz, 2H) 7.14 (dd,J=8.3, 4.6 Hz, 1H) 7.43 (d, J=8.3 Hz, 2H) 7.55 (d, J=8.2 Hz, 1H) 8.04(s, 1H) 8.48 (d, J=4.5 Hz, 1H) 9.01 (d, J=6.5 Hz, 1H)

Example 57:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of3-iodo-1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-pyrrolo[3,2-b]pyridine(made by alkylation of Intermediate 1, using a method analogous to thatdescribed in Intermediate 18), (200 mg), palladium (II) acetate (3 mg),XantPhos (7 mg), (1S,2S)-2-aminocyclohexanol hydrochloride (226 mg),sodium carbonate (200 mg) and toluene (5 mL) were purged with CO thenheated to 80° C. overnight. The reaction mixture was filtered and thefiltrate was reduced in vacuo. The residue was purified by columnchromatography to give the desired compound (55 mg).

LCMS: m/z 430.30 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): ppm 1.10-1.39 (m, 4H) 1.55-1.70 (m, 2H)1.81-2.05 (m, 2H) 3.35-3.45 (m, 1H) 3.68-3.78 (m, 1H) 3.84 (s, 3H) 4.81(d, J=5.2H, 1H) 5.50 (s, 2H) 7.24-7.34 (m, 3H) 7.51 (d, J=8.0 Hz, 2H)7.81 (s, 1H) 8.06-8.14 (m, 2H) 8.41 (s, 1H) 8.49 (dd, J=4.8, 1.2 Hz, 1H)8.75 (d, J=7.6 Hz, 1H)

Example 58:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (160 mg), 1-(bromomethyl)-4-methoxybenzene (110 mg)and cesium carbonate (408 mg) in DMF (3 mL) was stirred at rt overnight.The crude product was diluted with MeOH and purified by columnchromatography followed by prep. LCMS to give the desired compound (86mg).

LCMS: m/z 414.20 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.99-1.61 (m, 4H) 1.79 (d, J=9.2 Hz, 2H)2.10-2.24 (m, 2H) 3.55 (td, J=9.9, 4.5 Hz, 1H) 3.80 (s, 3H) 3.83-3.95(m, 1H) 5.66 (s, 2H) 6.86 (d, J=8.4 Hz, 2H) 7.07 (d, J=8.4 Hz, 2H) 7.18(d, J=5.0 Hz, 1H) 8.06 (s, 1H) 8.35 (d, J=5.1 Hz, 1H) 9.04 (d, J=6.4 Hz,1H)

Example 59:1-((6-Chloropyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (150 mg), 2-chloro-5-(chloromethyl)pyridine (89 mg)and cesium carbonate (411 mg) in DMF (4.9 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (167 mg).

LCMS: m/z 399.57 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.20-1.58 (m, 4H) 1.70-1.82 (m, 2H)2.00-2.16 (m, 2H) 2.46 (s, 3H) 3.55 (td, J=9.8, 4.3 Hz, 1H) 3.84-4.00(m, 1H) 5.45-5.59 (m, 2H) 6.88 (d, J=4.8 Hz, 1H) 7.03-7.13 (m, 1H) 7.19(d, J=8.2 Hz, 1H) 8.11 (d, J=12.4 Hz, 2H) 8.33 (d, J=4.8 Hz, 1H) 9.26(d, J=7.0 Hz, 1H)

Example 60:1-(4-Chlorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (150 mg), 1-(bromomethyl)-4-chlorobenzene (113 mg)and cesium carbonate (411 mg) in DMF (4.9 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (107 mg).

LCMS: m/z 398.56 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.23-1.83 (m, 6H) 2.13 (d, J=8.1 Hz, 2H)2.56 (s, 3H) 3.70 (br. s., 1H) 3.87 (br. s., 1H) 5.52-5.63 (m, 2H) 6.89(d, J=8.2 Hz, 2H) 7.20-7.36 (m, 3H) 8.42 (br. s., 1H) 9.27 (d, J=5.9 Hz,1H)

Example 61:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (270 mg), 2-(chloromethyl)-5-methylpyridinehydrochloride (180 mg) and cesium carbonate (689 mg) in DMF (3 mL) wasstirred at rt overnight. The crude product was purified by prep. LCMSthen azeotroped with DCM to remove the residual AcOH to give the desiredcompound (141 mg).

LCMS: m/z 399.20 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.04-1.67 (m, 4H) 1.79 (d, J=9.2 Hz, 2H)1.97-2.21 (m, 2H) 2.32 (s, 3H) 3.56 (td, J=9.9, 4.5 Hz, 1H) 3.79-4.00(m, 1H) 5.61-5.98 (m, 2H) 6.69 (d, J=8.0 Hz, 1H) 7.17 (d, J=5.1 Hz, 1H)7.41 (d, J=7.7 Hz, 1H) 8.14 (s, 1H) 8.35 (d, J=5.1 Hz, 1H) 8.41 (s, 1H)9.04 (d, J=6.5 Hz, 1H)

Example 62:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (250 mg), 5-(chloromethyl)-2-methylpyridinehydrochloride (167 mg) and cesium carbonate (638 mg) in DMF (3 mL) wasstirred at rt overnight. The crude product was diluted with EtOAc (60mL) and washed with water (2×20 mL) and brine (20 mL). The combinedaqueous layers were extracted with EtOAc (20 mL) and the combinedorganic layers were dried over MgSO₄, filtered and evaporated in vacuo.The residue was purified by column chromatography to give the desiredcompound (191 mg).

LCMS: m/z 399.24 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.01-1.64 (m, 4H) 1.79 (d, J=9.4 Hz, 2H)2.06-2.19 (m, 2H) 2.55 (s, 3H) 3.55 (td, J=9.9, 4.5 Hz, 1H) 3.82-3.96(m, 1H) 4.24 (br. s., 1H) 5.71 (s, 2H) 7.11 (d, J=8.1 Hz, 1H) 7.19 (d,J=5.3 Hz, 1H) 7.23 (dd, J=8.0, 2.1 Hz, 1H) 8.09 (s, 1H) 8.36 (d, J=5.1Hz, 1H) 8.40 (d, J=1.6 Hz, 1H) 9.01 (d, J=6.4 Hz, 1H)

Example 63:N-((1S,2S)-2-Hydroxycyclohexyl)-7-methyl-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 1-(chloromethyl)-4-methylbenzene (37 μl)and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (103 mg).

LCMS: m/z 378.65 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.64 (m, 4H) 1.78 (br. s., 2H)2.07-2.19 (m, 2H) 2.31 (s, 3H) 2.51 (s, 3H) 3.57 (td, J=9.8, 4.3 Hz, 1H)3.83-3.96 (m, 1H) 4.69 (br. s., 1H) 5.49 (s, 2H) 6.78-6.91 (m, 3H) 7.10(d, J=7.8 Hz, 2H) 8.00 (s, 1H) 8.32 (d, J=4.7 Hz, 1H) 9.28 (d, J=6.1 Hz,1H)

Example 64:N-((1S,2S)-2-Hydroxycyclohexyl)-7-methyl-1-((5-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 2-(chloromethyl)-5-methylpyridinehydrochloride (72 mg) and cesium carbonate (302 mg) in DMF (3.6 mL) wasstirred at rt overnight. The reaction mixture was filtered and thefiltrate was reduced in vacuo. The residue was purified by columnchromatography to give the desired compound (142 mg).

LCMS: m/z 379.63 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.20-1.87 (m, 6H) 2.15 (d, J=11.5 Hz, 2H)2.32 (s, 3H) 2.53 (s, 3H) 3.60 (d, J=3.3 Hz, 1H) 3.83-3.98 (m, 1H)5.56-5.69 (m, 2H) 6.56 (d, J=6.2 Hz, 1H) 6.92 (d, J=3.9 Hz, 1H) 7.39 (d,J=7.7 Hz, 1H) 8.35 (d, J=4.7 Hz, 1H) 8.42 (s, 1H) 9.28 (d, J=6.4 Hz, 1H)

Example 65:1-(3-Fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 1-(bromomethyl)-3-fluorobenzene (76 mg) andcesium carbonate (302 mg) in DMF (3.6 mL) was stirred at rt overnight.The reaction mixture was filtered and the filtrate was reduced in vacuo.The residue was purified by column chromatography to give the desiredcompound (127 mg).

LCMS: m/z 382.62 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.22-1.62 (m, 4H) 1.78 (d, J=2.9 Hz, 2H)2.06-2.19 (m, 2H) 2.48 (s, 3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.82-3.97(m, 1H) 4.60 (br. s., 1H) 5.53 (s, 2H) 6.62 (d, J=9.4 Hz, 1H) 6.70 (d,J=7.7 Hz, 1H) 6.89 (d, J=4.8 Hz, 1H) 6.93-7.02 (m, 1H) 7.22-7.33 (m, 1H)8.01 (s, 1H) 8.33 (d, J=4.8 Hz, 1H) 9.26 (d, J=6.4 Hz, 1H)

Example 66:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(4-methoxy-3-methylbenzyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 4-(chloromethyl)-1-methoxy-2-methylbenzene(69 mg) and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (126 mg).

LCMS: m/z 408.65 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.17-1.63 (m, 4H) 1.76 (br. s., 2H)2.06-2.18 (m, 5H) 2.54 (s, 3H) 3.56 (td, J=9.8, 4.5 Hz, 1H) 3.78 (s, 3H)3.81-3.94 (m, 1H) 4.75 (br. s., 1H) 5.40 (s, 2H) 6.65-6.81 (m, 3H) 6.86(d, J=4.8 Hz, 1H) 7.96 (s, 1H) 8.30 (d, J=4.8 Hz, 1H) 9.27 (d, J=6.4 Hz,1H)

Example 67:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (120 mg), 5-(chloromethyl)-2-methoxypyridine (69 mg)and cesium carbonate (329 mg) in DMF (3.9 mL) was stirred at rtovernight. A further 20 mg 5-(chloromethyl)-2-methoxypyridine was addedand stirred for 2 days. A further 100 mg5-(chloromethyl)-2-methoxypyridine was added and stirred for 24 h. Water(20 mL) was added and the reaction mixture was extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (20 mL)and dried over MgSO₄, filtered and evaporated in vacuo. The residue waspurified by column chromatography to give the desired compound (131 mg).

LCMS: m/z 395.49 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.15-1.52 ppm (m, 4H) 1.71 (d, J=9.9 Hz, 2H)2.05 (t, J=9.0 Hz, 2H) 2.50 (s, 3H) 3.16 (br. s., 1H) 3.49 (td, J=9.7,4.3 Hz, 1H) 3.71-3.84 (m, 1H) 3.83 (s, 3H) 5.43 (s, 2H) 6.62 (d, J=8.6Hz, 1H) 6.84 (d, J=4.8 Hz, 1H) 7.10 (dd, J=8.6, 2.1 Hz, 1H) 7.79 (d,J=1.8 Hz, 1H) 7.95 (s, 1H) 8.25 (d, J=4.6 Hz, 1H) 9.24 (d, J=7.0 Hz, 1H)

Example 68:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((6-methoxypyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (160 mg), 5-(chloromethyl)-2-methoxypyridine (94 mg)and cesium carbonate (408 mg) in DMF (3 mL) was stirred at rt overnight.The crude product was purified by prep. LCMS then azeotroped with DCM toremove the residual AcOH to give the desired compound (111 mg).

LCMS: m/z 415.21 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.05-1.64 (m, 4H) 1.79 (d, J=9.5 Hz, 2H)2.02-2.28 (m, 2H) 3.56 (td, J=9.9, 4.5 Hz, 1H) 3.70-4.09 (m, 1H) 3.93(s, 3H) 5.67 (s, 2H) 6.72 (d, J=8.6 Hz, 1H) 7.21 (d, J=5.1 Hz, 1H) 7.34(dd, J=8.6, 2.3 Hz, 1H) 8.04 (s, 1H) 8.11 (s, 1H) 8.37 (d, J=5.1 Hz, 1H)9.02 (d, J=6.5 Hz, 1H)

Example 69:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (160 mg), 5-(chloromethyl)-2-methoxypyridine (94 mg)and cesium carbonate (408 mg) in DMF (3 mL) was stirred at rt overnight.The crude product was purified by prep. LCMS then azeotroped with DCM toremove the residual AcOH to give the desired compound (116 mg).

LCMS: m/z 415.21 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.12-1.64 (m, 4H) 1.80 (d, J=9.3 Hz, 2H)2.01-2.17 (m, 2H) 3.58 (td, J=9.9, 4.3 Hz, 1H) 3.79-4.03 (m, 1H) 3.91(s, 3H) 5.67 (s, 2H) 6.28 (s, 1H) 6.55 (d, J=4.9 Hz, 1H) 7.19 (d, J=5.1Hz, 1H) 7.98-8.22 (m, 2H) 8.38 (d, J=5.3 Hz, 1H) 9.03 (d, J=6.6 Hz, 1H)

Example 70:7-Chloro-1-((6-cyanopyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 5-(bromomethyl)picolinonitrile (111 mg) andcesium carbonate (383 mg) in DMF (3 mL) was stirred at rt overnight. Thecrude product was purified by prep. LCMS then azeotroped with DCM toremove the residual AcOH to give the desired compound (125 mg).

LCMS: m/z 410.19 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.17-1.64 (m, 4H) 1.80 (d, J=9.7 Hz, 2H)2.02-2.26 (m, 2H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.82-4.04 (m, 1H) 5.83(s, 2H) 7.21 (d, J=5.0 Hz, 1H) 7.37 (dd, J=8.0, 1.5 Hz, 1H) 7.64 (d,J=8.1 Hz, 1H) 8.17 (s, 1H) 8.41 (d, J=4.9 Hz, 1H) 8.56 (s, 1H) 9.00 (d,J=6.6 Hz, 1H)

Example 71:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 4-(chloromethyl)-2-methoxypyridine (63 mg)and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (63 mg).

LCMS: m/z 395.68 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.29-1.62 (m, 4H) 1.70-1.95 (m, 2H)2.08-2.21 (m, 2H) 2.47 (s, 3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.84-3.94(m, 1H) 3.89 (s, 3H) 5.48 (s, 2H) 6.19 (s, 1H) 6.46 (d, J=5.4 Hz, 1H)6.90 (d, J=4.7 Hz, 1H) 8.01 (s, 1H) 8.09 (d, J=5.4 Hz, 1H) 8.34 (d,J=4.7 Hz, 1H) 9.24 (d, J=6.4 Hz, 1H)

Example 72:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 4-(chloromethyl)-1-methyl-1H-pyrazolehydrochloride (94 mg) and cesium carbonate (383 mg) in DMF (3 mL) wasstirred at rt weekend. The crude product was purified by prep. LCMS thenazeotroped with DCM to remove the residual AcOH to give the desiredcompound (101 mg).

LCMS: m/z 388.18 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.19-1.62 (m, 4H) 1.79 (d, J=9.5 Hz, 2H)2.11 (d, J=8.2 Hz, 2H) 3.55 (td, J=9.9, 4.5 Hz, 1H) 3.73-4.02 (m, 1H)3.87 (s, 3H) 5.60 (s, 2H) 7.21 (d, J=5.1 Hz, 1H) 7.30 (s, 1H) 7.46 (s,1H) 8.12 (s, 1H) 8.35 (d, J=5.3 Hz, 1H) 9.02 (d, J=6.2 Hz, 1H)

Example 73:N-((1S,2S)-2-Hydroxycyclohexyl)-7-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 4-(chloromethyl)-1-methyl-1H-pyrazole (53mg) and cesium carbonate (302 mg) in DMF (3.6 mL) was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasreduced in vacuo. The residue was purified by column chromatography togive the desired compound (59 mg).

LCMS: m/z 368.67 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.16-1.56 (m, 4H) 1.66 (br. s., 2H)1.92-2.10 (m, 2H) 2.56 (s, 3H) 3.49 (td, J=9.8, 4.3 Hz, 1H) 3.75 (s, 3H)3.79-3.93 (m, 1H) 5.27 (s, 2H) 6.82 (d, J=4.7 Hz, 1H) 7.09 (s, 1H)7.17-7.22 (m, 1H) 8.00 (s, 1H) 8.24 (d, J=4.9 Hz, 1H) 9.15 (d, J=7.1 Hz,1H)

Example 74:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 2-(bromomethyl)-4-methylthiazole (118 mg)and cesium carbonate (383 mg) in DMF (3 mL) was stirred at rt overnight.The crude product was purified by prep. LCMS to give the desiredcompound (125 mg).

LCMS: m/z 405.57 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.20-1.40 (m, 4H) 1.55-1.74 (m, 2H) 1.89(d, J=10.3 Hz, 1H) 2.04 (d, J=10.3 Hz, 1H) 2.35 (s, 3H) 3.34-3.46 (m,1H) 3.72 (d, J=8.3 Hz, 1H) 4.78 (d, J=5.1 Hz, 1H) 6.04 (s, 2H) 7.35-7.42(m, 2H) 8.40-8.50 (m, 2H) 8.74 (d, J=7.6 Hz, 1H)

Example 75:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((5-methylthiazol-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 2-(bromomethyl)-5-methylthiazole (118 mg)and cesium carbonate (383 mg) in DMF (3 mL) was stirred at rt overnight.The crude product was purified by prep. LCMS to give the desiredcompound (113 mg).

LCMS: m/z 405.57 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.18-1.39 (m, 4H) 1.52-1.74 (m, 2H) 1.89(d, J=10.0 Hz, 1H) 2.04 (d, J=9.3 Hz, 1H) 2.35 (s, 3H) 3.33-3.46 (m, 1H)3.72 (d, J=8.3 Hz, 1H) 4.78 (d, J=5.3 Hz, 1H) 6.04 (s, 2H) 7.32-7.44 (m,2H) 8.43 (d, J=5.1 Hz, 1H) 8.46 (s, 1H) 8.74 (d, J=7.6 Hz, 1H)

Example 76:N-((1S,2S)-2-Hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (70 mg), 2-methyl-4-(bromomethyl)pyridine (50 mg) andcesium carbonate (220 mg) in DMF (2 mL) was stirred at rt overnight. Thereaction mixture was filtered thought Celite and concentrated in vacuo.The residue was triturated with small amount of MeOH to afford thedesired compound (19 mg).

LCMS: m/z 365.23 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.20-1.37 (m, 4H) 1.57-1.67 (m, 2H)1.82-1.91 (m, 1H) 2.02 (d, J=10.2 Hz, 1H) 2.38 (s, 3H) 3.39 (d, J=4.3Hz, 1H) 3.71 (d, J=8.4 Hz, 1H) 4.79 (d, J=3.9 Hz, 1H) 5.53 (s, 2H) 6.92(d, J=4.7 Hz, 1H) 7.05 (s, 1H) 7.25 (dd, J=8.4, 4.7 Hz, 1H) 7.97 (d,J=8.2 Hz, 1H) 8.34 (d, J=5.1 Hz, 1H) 8.38 (s, 1H) 8.48 (d, J=4.5 Hz, 1H)8.74 (d, J=7.6 Hz, 1H)

Example 77:N-((1S,2S)-2-Hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 4), (70 mg), 4-(chloroomethyl)pyridine hydrochloride (44mg) and cesium carbonate (220 mg) in DMF (2 mL) was stirred at rtovernight. The reaction mixture was filtered thought Celite andconcentrated in vacuo. The residue was triturated with small amount ofMeOH to afford the desired compound (26 mg).

LCMS: m/z 351.17 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.19-1.37 (m, 4H) 1.56-1.68 (m, 2H) 1.87(d, J=7.8 Hz, 1H) 2.02 (d, J=9.6 Hz, 1H) 3.40 (br. s., 1H) 3.71 (d,J=8.0 Hz, 1H) 4.79 (d, J=5.1 Hz, 1H) 5.59 (s, 2H) 7.13 (d, J=5.5 Hz, 2H)7.25 (dd, J=8.2, 4.7 Hz, 1H) 7.98 (d, J=8.2 Hz, 1H) 8.40 (s, 1H) 8.48(d, J=4.5 Hz, 3H) 8.75 (d, J=7.6 Hz, 1H)

Example 78:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((2-methylpyridin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 2-methyl-4-(bromomethyl)pyridine (95 mg)and cesium carbonate (416 mg) in DMF (3 mL) was stirred at rt overnight.The reaction mixture was filtered thought Celite and concentrated invacuo. The residue was triturated with small amount of MeOH to affordthe desired compound (87 mg).

LCMS: m/z 399.20 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.28 (d, J=6.8 Hz, 4H) 1.55-1.69 (m, 2H)1.86 (br. s., 1H) 2.03 (d, J=9.8 Hz, 1H) 2.37 (s, 3H) 3.36-3.46 (m, 1H)3.71 (d, J=8.0 Hz, 1H) 4.80 (d, J=4.5 Hz, 1H) 5.79 (s, 2H) 6.70 (d,J=4.7 Hz, 1H) 6.85 (s, 1H) 7.35 (d, J=5.1 Hz, 1H) 8.33 (d, J=5.1 Hz, 1H)8.42 (d, J=5.1 Hz, 1H) 8.48 (s, 1H) 8.76 (d, J=7.4 Hz, 1H)

Example 79:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (150 mg), 4-(chloroomethyl)pyridine hydrochloride (84mg) and cesium carbonate (416 mg) in DMF (3 mL) was stirred at rtovernight. The reaction was incomplete by LC-MS, so an additional4-(chloroomethyl)pyridine hydrochloride (84 mg) and cesium carbonate(416 mg) were added and the reaction was stirred at rt 2 d. The reactionmixture was filtered thought Celite and concentrated in vacuo. Theresidue was triturated with small amount of MeOH to afford the desiredcompound (10 mg).

LCMS: m/z 385.18 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.28 (br. s., 4H) 1.65 (br. s., 2H) 1.87(br. s., 1H) 2.04 (br. s., 1H) 3.39 (br. s., 1H) 3.62-3.80 (m, 1H) 4.79(br. s., 1H) 5.84 (br. s., 2H) 6.93 (d, J=3.1 Hz, 2H) 7.35 (d, J=4.3 Hz,1H) 8.30-8.58 (m, 4H) 8.76 (d, J=6.8 Hz, 1H)

Example 80:7-Chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-((4-methylpyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 17), (160 mg), 2-(chloromethyl)-4-methylpyridinehydrochloride (107 mg) and cesium carbonate (408 mg) in DMF (42 uL) wasstirred at rt overnight. The crude product was purified by prep. LCMSthen azeotroped with DCM to remove the residual AcOH to to give thedesired compound (123 mg).

LCMS: m/z 399.64 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 0.84-2.02 (m, 6H) 2.11-2.21 (m, 2H) 2.27 (s,3H) 3.57 (td, J=9.9, 4.4 Hz, 1H) 3.77-4.00 (m, 1H) 4.01-4.70 (m, 1H)5.63-5.99 (m, 2H) 6.59 (s, 1H) 7.05 (d, J=4.7 Hz, 1H) 7.18 (d, J=5.1 Hz,1H) 8.14 (s, 1H) 8.37 (d, J=5.1 Hz, 1H) 8.44 (d, J=5.0 Hz, 1H) 9.06 (d,J=6.6 Hz, 1H)

Example 81:1-((5-Chloropyridin-2-yl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture ofN-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 13), (110 mg), 5-chloro-2-(chloromethyl)pyridine (65 mg),sodium iodide (1 mg) and cesium carbonate (302 mg) in DMF (3.6 mL) wasstirred at 40° C. overnight. The reaction mixture was diluted with EtOAcand filtered and the filtrate was reduced in vacuo. The residue waspurified by column chromatography to give the desired compound (13 mg).

LCMS: m/z 399.62 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.23-1.65 (m, 4H) 1.70-1.92 (m, 2H)2.09-2.29 (m, 2H) 2.49 (s, 3H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.76-4.03(m, 1H) 5.53-5.71 (m, 2H) 6.59 (d, J=8.3 Hz, 1H) 6.90 (d, J=4.9 Hz, 1H)7.54 (dd, J=8.4, 2.3 Hz, 1H) 8.06 (s, 1H) 8.33 (d, J=4.7 Hz, 1H) 8.54(d, J=2.2 Hz, 1H) 9.25 (d, J=6.6 Hz, 1H)

Example 82:1-(4-Fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 74), (90 mg)), in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and reduced in vacuo. The residue was dissolved in DMF(2.4 mL) and the resultant solution was stirred at rt under nitrogen. Tothis solution was added 1-(bromomethyl)-4-fluorobenzene (45.3 mg) andCs₂CO₃ (180 mg) and the reaction was stirred at rt under nitrogenovernight. The solid was filtered and the filtrate was concentratedunder reduced pressure and purified by column chromatography (normalphase, Biotage SNAP cartridge KP-Sil, gradient 20% to 100% EtOAc inn-hexane, followed by 0-10% Methanol in EtOAc). The major band to elutewas then subjected to chiral chromatographic separation usingpreparative IE column (i.d. 20 mm; length 250 mm) and 97% DCM, 3% EtOH(v/v) as eluent, injection volume: 1500 microL, flow rate: 18.0 mL/min,oven temperature: 30° C., which afforded the two major eluting peaks.

The first eluting peak afforded1-(4-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (33 mg).

Specific optical rotation [α]_(D): +37.8 (25° C., MeOH)

LCMS: m/z 384.58 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.86-1.98 (m, 1H) 2.11 (m, 1H) 2.53 (s, 3H)3.25 (dd, J=11.3, 9.8 Hz, 1H) 3.50 (td, J=11.9, 2.2 Hz, 1H) 3.70 (td,J=9.4, 4.9 Hz, 1H) 3.98-4.07 (m, 2H) 4.12 (dd, J=11.5, 4.9 Hz, 1H) 5.54(s, 2H) 6.91-7.05 (m, 5H) 8.06 (br. s., 1H) 8.36 (d, J=4.9 Hz, 1H) 9.43(d, J=5.6 Hz, 1H)

Example 83:1-(4-Methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 74), (72 mg) in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and concentrated under vacuum. The residue was dissolvedin DMF (1.9 mL) and the resultant solution was stirred at rt undernitrogen. To this solution was added 1-(bromomethyl)-4-methoxybenzene(39 mg) and Cs₂CO₃ (144 mg) and the reaction was stirred at rt undernitrogen overnight. The solid was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography (normal phase, Biotage SNAP cartridge KP-Sil, gradient20% to 100% EtOAc in n-hexane, followed by 0-10% Methanol in EtOAc).Chiral chromatographic separation of the major eluting peak usingpreparative IE column (i.d. 20 mm; length 250 mm) and 96% DCM, 4% EtOH(v/v) as eluent, injection volume: 1500 microL, flow rate: 18.0 mL/min,oven temperature: 30 C, afforded the two major eluting peaks.

The first eluting peak afforded1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (10 mg).

Specific optical rotation [α]_(D): +37.4 (25° C., MeOH)

LCMS: m/z 396.62 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.93 (d, J=9.1 Hz, 1H) 2.10-2.14 (m, 1H)2.56-2.61 (m, 3H) 3.25 (t, J=10.6 Hz, 1H) 3.49 (t, J=11.6 Hz, 1H) 3.73(br. s., 1H) 3.76 (br. s., 1H) 3.79 (s, 3H) 3.99-4.06 (m, 2H) 4.12 (dd,J=11.2, 4.7 Hz, 1H) 5.52 (s, 2H) 6.85 (d, J=8.8 Hz, 2H) 6.91 (d, J=8.5Hz, 2H) 6.96 (br. s., 1H) 8.04 (br. s., 1H) 8.37 (br. S., 1H) 9.44 (br.s., 1H)

Example 84:1-(3-Fluoro-4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 74), (72 mg)), in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and reduced in vacuo. The residue was dissolved in DMF(1.9 mL) and the resultant solution was stirred at rt under nitrogen. Tothis solution was added 4-(bromomethyl)-2-fluoro-1-methoxybenzene (42.0mg,) and Cs₂CO₃ (144 mg) and the reaction was stirred at rt undernitrogen overnight. The solid was filtered and the filtrate wasconcentrated under reduced pressure and purified by columnchromatography (normal phase, Biotage SNAP cartridge KP-Sil, gradient20% to 100% EtOAc in n-hexane, followed by 0-10% Methanol in EtOAc). Themajor peak to elute was subjected to chiral chromatographic separationusing preparative IE column (i. d. 20 mm; length 250 mm) and 97% DCM, 3%EtOH (v/v) as eluent, injection volume: 1500 microL, flow rate: 18.0mL/min, oven temperature: 30° C., which afforded the two major elutingpeaks.

The first eluting peak afforded1-(3-fluoro-4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (19 mg).

Specific optical rotation [α]_(D): +31.5 (25° C., MeOH)

LCMS: m/z 414.59 [M+H]⁺.

1H NMR (400 MHz, CDCl₃): ppm 1.93 (td, J=12.4, 4.7 Hz, 1H) 2.08-2.16 (m,1H) 2.54 (s, 3H) 3.25 (dd, J=11.1, 10.2 Hz, 1H) 3.49 (td, J=11.8, 2.1Hz, 1H) 3.70 (td, J=9.4, 4.9 Hz, 1H) 3.86-3.88 (m, 3H) 3.96-4.06 (m, 2H)4.11 (dd, J=11.6, 5.3 Hz, 1H) 5.48 (s, 2H) 6.64 (d, J=8.6 Hz, 1H) 6.71(d, J=11.7 Hz, 1H) 6.89 (d, J=11.7 Hz, 1H) 6.93 (d, J=8.6 Hz, 1H) 8.05(br. s., 1H) 8.36 (d, J=4.9 Hz, 1H) 9.42 (d, J=5.6 Hz, 1H)

Example 85:N-(trans-3-Hydroxytetrahydro-2H-pyran-4-yl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 74), (74 mg) in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and concentrated under vacuum. The residue was dissolvedin DMF (1.9 mL) and the resultant solution was stirred at rt undernitrogen. To this solution was added 4-(chloromethyl)-2-methoxypyridine(31 mg) and Cs₂CO₃ (148 mg) and the reaction was stirred at rt undernitrogen overnight. The solid was filtered and the filtrate wasconcentrated under vacuum and purified by column chromatography (normalphase, Biotage SNAP cartridge KP-Sil, gradient 0% to 100% EtOAc inn-hexane, followed by 0-10% Methanol in EtOAc). Chiral chromatographicseparation using preparative IE column (i.d. 20 mm; length 250 mm) and98% DCM, 2% EtOH (v/v) as eluent, injection volume: 1500 microL, flowrate: 18.0 mL/min, oven temperature: 30° C., afforded the two majoreluting peaks.

The first eluting peak affordedN-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1-((2-methoxypyridin-4-yl)methyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (25 mg).

LCMS: m/z 397.58 [M+H]⁺.

Specific optical rotation [α]_(D): +38.0 (25° C., MeOH)

¹H NMR (400 MHz, CDCl₃) ppm 1.92 (qd, J=12.2, 4.4 Hz, 1H) 2.11-2.15 (m,1H) 2.50-2.54 (m, 3H) 3.26 (t, J=10.6 Hz, 1H) 3.48-3.53 (m, 1H)3.71-3.77 (m, 1H) 3.90 (s, 3H) 4.00-4.06 (m, 2H) 4.12 (dd, J=11.3, 4.8Hz, 1H) 5.53 (s, 2H) 6.20 (s, 1H) 6.49 (d, J=5.3 Hz, 1H) 6.95-7.00 (m,1H) 8.12 (d, J=5.3 Hz, 1H) 8.40 (d, J=4.4 Hz, 1H) 9.40 (d, J=4.7 Hz, 1H)

Example 86:7-Chloro-1-(3-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl7-chloro-3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 75), (112 mg) in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and reduced in vacuo. The residue was dissolved in DMF(2.74 mL) and the resultant solution was stirred at rt under nitrogen.To this solution was added 1-(chloromethyl)-3-fluorobenzene (38.9 mg)and Cs₂CO₃ (212 mg) and the reaction was stirred at rt under nitrogenovernight. The solid was filtered and the filtrate was concentratedunder vacuum and purified by column chromatography (normal phase,Biotage SNAP cartridge KP-Sil, gradient 20% to 100% EtOAc in n-hexane,followed by 0-10% Methanol in EtOAc). Chiral chromatographic separationof the major eluting peak using preparative IE column (i.d. 20 mm;length 250 mm) and 97% DCM, 3% EtOH (v/v) as eluent, injection volume:1500 microL, flow rate: 18.0 mL/min, oven temperature: 30° C., affordedthe two major eluting peaks.

The first eluting peak afforded7-chloro-1-(3-fluorobenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (18 mg).

Specific optical rotation [α]_(D): +39.2 (25° C., MeOH)

LCMS: m/z 404.53 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.83-1.95 (m, 1H) 2.09 (m, 1H) 3.24 (dd,J=11.4, 9.9 Hz, 1H) 3.48 (td, J=11.9, 2.2 Hz, 1H) 3.70 (td, J=9.5, 5.0Hz, 1H) 3.95-4.05 (m, 2H) 4.10 (dd, J=11.6, 4.8 Hz, 1H) 5.72 (s, 2H)6.73-6.79 (m, 1H) 6.85 (d, J=7.6 Hz, 1H) 7.00 (td, J=8.4, 2.0 Hz, 1H)7.23 (d, J=5.4 Hz, 1H) 7.30 (td, J=8.0, 5.9 Hz, 1H) 8.18 (s, 1H) 8.42(d, J=5.4 Hz, 1H) 9.16 (d, J=5.9 Hz, 1H)

Example 87:7-Chloro-1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

To a solution of tert-butyl7-chloro-3-((trans-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(Intermediate 75), (100 mg) in DCM (5 mL) stirred at rt under nitrogenwas added TFA (5 mL) and the reaction was stirred at rt for 1.5 h. Thereaction was concentrated under vacuum and the residue was dissolved inMeOH (5 mL) and loaded onto an SCX cartridge, washing with MeOH (5 CV)and eluting with 2M NH3/MeOH (10 CV). The ammonia-containing fractionswere combined and reduced in vacuo. The residue was dissolved in DMF(2.45 mL) and the resultant solution was stirred at rt under nitrogen.To this solution was added 1-(chloromethyl)-4-methoxybenzene (39.6 mg)and Cs₂CO₃ (189 mg) and the reaction was stirred at rt under nitrogenovernight. The solid was filtered and the filtrate was concentratedunder vacuum and purified by column chromatography (normal phase,Biotage SNAP cartridge KP-Sil, gradient 20% to 100% EtOAc in n-hexane,followed by 0-10% Methanol in EtOAc). Chiral chromatographic separationof the major eluting peak using preparative IE column (i.d. 20 mm;length 250 mm) and 97% DCM, 3% EtOH (v/v) as eluent, injection volume:1500 microL, flow rate: 18.0 mL/min, oven temperature: 30° C., affordedthe two major eluting peaks.

The first eluting peak afforded7-chloro-1-(4-methoxybenzyl)-N-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,a single enantiomer of trans relative stereochemistry but unknownabsolute configuration, (17 mg).

Specific optical rotation [α]_(D): +38.3 (25° C., MeOH)

LCMS: m/z 416.54 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) ppm 1.83-1.96 (m, 1H) 2.09 (m, 1H) 3.24 (dd,J=11.3, 9.8 Hz, 1H) 3.49 (td, J=11.9, 2.5 Hz, 1H) 3.69 (td, J=9.5, 5.0Hz, 1H) 3.79-3.81 (m, 3H) 3.95-4.05 (m, 2H) 4.11 (dd, J=11.5, 4.9 Hz,1H) 5.67 (s, 2H) 6.85-6.90 (m, 2H) 7.08 (s, 1H) 7.10 (d, J=7.7 Hz, 1H)7.23 (d, J=7.7 Hz, 1H) 8.12 (s, 1H) 8.38 (d, J=5.4 Hz, 1H) 9.18 (d,J=5.6 Hz, 1H)

Example 88:7-Chloro-1-(4-fluorobenzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 78), (70 mg), 4-fluorobenzyl bromide (49 mg) and cesiumcarbonate (193 mg) in DMF (3 mL) was stirred at rt overnight. Thereaction mixture was filtered thought Celite and concentrated in vacuo.The residue was triturated with small amount of MeOH to afford thedesired compound (71 mg).

LCMS: m/z 404.11 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.61 (d, J=10.9 Hz, 1H) 1.80-1.95 (m, 1H)3.42 (t, J=10.5 Hz, 1H) 3.51 (d, J=11.9 Hz, 1H) 3.64 (br. s., 1H)3.68-3.83 (m, 2H) 4.14 (br. s., 1H) 5.13 (br. s., 1H) 5.77 (s, 2H)7.04-7.17 (m, 4H) 7.35 (d, J=5.1 Hz, 1H) 8.41 (d, J=5.1 Hz, 1H) 8.50 (s,1H) 8.97 (d, J=8.0 Hz, 1H)

Example 89:7-Chloro-1-(4-fluorobenzyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of7-chloro-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(Intermediate 80), (77 mg), 4-fluorobenzyl bromide (54 mg) and cesiumcarbonate (212 mg) in DMF (3 mL) was stirred at rt overnight. Thereaction mixture was filtered thought Celite and concentrated in vacuo.The residue was triturated with small amount of MeOH to afford thedesired compound (57 mg).

LCMS: m/z 404.15 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) ppm 1.61 (d, J=11.3 Hz, 1H) 1.87 (d, J=8.4 Hz,1H) 3.38-3.47 (m, 1H) 3.51 (d, J=11.3 Hz, 1H) 3.64 (br. s., 1H)3.68-3.82 (m, 2H) 4.14 (br. s., 1H) 5.15 (br. s., 1H) 5.77 (br. s., 2H)7.04-7.18 (m, 4H) 7.35 (d, J=4.5 Hz, 1H) 8.41 (d, J=4.7 Hz, 1H) 8.50(br. s., 1H) 8.97 (d, J=8.0 Hz, 1H)

Examples 90-105

The following Examples 90-105 were prepared by methods according oranalogous to those described herein above;

Example 90:N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 418.1 [M+H]⁺ Example 91:1-(4-fluoro-3-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 398.23 [M+H]⁺ Example 92:1-(2-fluoro-4-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 398.1 [M+H]⁺ Example 93:N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 380.18 [M+H]⁺ Example 94:1-(3,4-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 486.59 [M+H]⁺ Example 95:N-((1S,2S)-2-hydroxycyclohexyl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 418.60 [M+H]⁺ Example 96:N-((1S,2S)-2-hydroxycyclohexyl)-1-(3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 364.65 [M+H]⁺ Example 97:1-(2-fluoro-4-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 382.60 [M+H]⁺ Example 98:1-(2,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 400.60 [M+H]⁺ Example 99:7-chloro-N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 468.57 [M+H]⁺ Example 100:N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1-(4-(trifluoromethoxy)benzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 448.64 [M+H]⁺ Example 101:1-(3,5-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 400.62 [M+H]⁺ Examples 102:1-(2-fluoro-3-methoxybenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 398.66 [M+H]⁺ Example 103:N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methoxy-3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 394.69.15 [M+H]⁺ Examples 104:1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 416.65 [M+H]⁺ Example 105:N-((1S,2S)-2-hydroxycyclohexyl)-7-methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide;LCMS: m/z 410.70 [M+H]⁺

The chemical structures of Examples 1-105 are depicted in Table 1

TABLE 1 Example Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

Biological Data—In Vitro AnalysisIn Vitro Cellular Assay

Baby hamster kidney cells stably expressing human or rat mAChR M1 to M5were utilised for primary and selectivity profiling activities. mAChR M2and M4 cell lines also stably expressed the chimeric Gαqi5 G-protein.

Human mAChR M1, M3, M5 and rat M1 cells were grown in low glucoseDulbecco's Modified Eagle's Medium (DMEM) medium plus heat inactivated10% fetal bovine serum (HI FBS) and 500 μg/ml hygromycin B¹. Human mAChRM2 and M4 cells were maintained as above with² the addition of 500 μg/mlG418 to the media. Cells were maintained in culture at 37° C./5% CO₂ andpassaged twice weekly by treatment with 0.05% Trypsin/EDTA detachmentsolution, centrifugation (200 g, 5 min) and re-suspension in freshmedia. Following cell expansion, cells were cryopreserved at −80° C. bytreatment with 0.05% Trypsin/EDTA detachment solution, centrifugation(200 g, 5 min) and re-suspension of the pellet in freezing media (90% HIFBS/10% DMSO³) at 15E6 cells/ml⁴.

Prior to assaying, cells were prepared by thawing at 37° C. in a waterbath, centrifugation (200 g, 5 min) and re-suspension of the pellet infresh media. 15000 cells per well were seeded in black, clear bottomed384-well Greiner Bio-One plates in plating medium (DMEM/10% HI FBS) andincubated overnight at 37 C/5% CO₂.

On the day of the assay, media was removed from each well and replacedwith 50 μl⁵ assay buffer (HBSS with 20 mM HEPES and 2.5 mM Probenecid)containing the calcium indicator, Calcium 4 (Molecular Devices). Cellswere then incubated at 37° C./5% CO₂ for 30 min and at room temperature.

Compound preparation was carried out by generation of 11-point, 1 in 3serial dilution concentration response curves in 100% DMSO. Compound wasthen diluted 1 in 65⁶ with assay buffer (HBSS with 20 mM HEPES and 2.5mM Probenecid) prior to the addition of 10 ul⁷ to the cells using aTetra fluorometric imaging plate reader (Molecular Devices)⁸. Compounddriven increases in intracellular calcium flux was measured as anincrease in fluorescence (494_(Ex), 516_(Em))⁹. Agonist pEC₅₀ values foreach compound were determined and agonist Emax values were generated inrelation to the maximum effect obtained by carbachol (100%).

Following agonist data acquisition, cells were then incubated for afurther 30 min at room temperature before either an EC₂₀ concentration(to measure positive allosteric modulator activity) or an EC₅₀concentration (to measure antagonism) of carbachol was added using afluorometric imaging plate reader. Positive allosteric modulator pEC₅₀values and antagonist pIC₅₀ values for each compound were thendetermined. PAM Emax values were generated following normalisationbetween the EC₂₀ base line fluorescence (0%) and maximal carbacholeffect (100%). Antagonist Emax values were generated followingnormalisation between the EC₈₀ fluorescence (0%) and baseline EC₀ (DMSO)response (100%). Data analysis was carried out using a 4 parameterlogistic nonlinear regression model with the XLFIT (IDBS) exceladd-in¹⁰. ¹⁻¹⁰ Examples 76-80 and 82-89 were tested in a slightlymodified procedure. The points of modification and the alternatereagents, concentrations or equipment employed in these examples were:¹200 μg/ml hygromycin B; ²G418 not added; ³CELLBANKER 1; ⁴10E6; ⁵ 40 μl;⁶ 1 in 99; ⁷ 20 μl; ⁸FDSS6000 (Hamamatsu Photonics); ⁹(480_(Ex),540_(Em)); ¹⁰Spotfire (TIBCO).

As measured by the above in vitro assay, compound Examples 1 to 105 arepositive allosteric modulators of mAChR M1 displaying the pEC50 valuesfor positive allosteric modulation given in Table 2.

TABLE 2 Example pEC₅₀  1 7.0  2 6.7  3 6.8  4 6.8  5 6.9  6 6.7  7 5.9 8 6.5  9 6.6 10 7.7 11 6.9 12 7.7 13 7.9 14 7.3 15 7.0 16 6.5 17 6.9 186.1 19 6.0 20 6.1 21 5.7 22 6.5 23 6.6 24 6.5 25 6.2 26 6.1 27 6.1 286.6 29 5.8 30 6.5 31 6.5 32 6.7 33 7.0 34 6.9 35 6.1 36 6.3 37 6.7 385.8 39 6.0 40 6.5 41 6.5 42 7.0 43 8.0 44 6.9 45 7.5 46 6.5 47 7.6 486.7 49 5.6 50 6.4 51 6.3 52 6.7 53 6.2 54 7.5 55 6.7 56 6.5 57 7.6 587.7 59 7.4 60 7.8 61 7.0 62 7.4 63 7.6 64 7.2 65 7.7 66 7.9 67 7.5 687.7 69 8.0 70 7.0 71 7.9 72 7.8 73 7.9 74 6.7 75 6.6 76 6.4 77 6.3 787.8 79 7.4 80 7.1 81 7.2 82 7.8 83 8.0 84 7.9 85 7.3 86 7.6 87 7.9 886.4 89 6.6 90 6.6 91 6.3 92 6.4 93 6.9 94 6.6 95 6.1 96 6.7 97 6.9 987.0 99 6.7 100  6.8 101  7.0 102  6.4 103  6.8 104  6.3 105  6.7

Certain compounds were tested in PAM, NAM and agonist modes againstmAChR M2, M3, M4 and M5. All examples tested in these assaysdemonstrated selectivity for mAChR M1. For example, compound examples 5,6, 8, 10, 11, 12, 13, 34 and 47 were shown to have pIC₅₀ or pEC₅₀ values<5.0 against mAChR M2, M3, M4 and M5.

Biological Data—In Vivo Analysis

Novel Object Recognition Test

The Novel Object Recognition test (NOR) is based on the greaterspontaneous exploration of a novel object, compared with a familiarobject, observed in rodents (Behav. Brain Res., 1988, 31(1), 47-59). Thetest is considered a model of recognition memory and does not involveappetitive or aversive reinforcement. Therefore, it is considered to beanalogous to recognition memory tests used in human clinical testing.Male Lister Hooded rats were assessed for object recognition in a testapparatus comprising of a perspex test arena housed within a soundattenuating chamber. Video images of behaviour were captured by digitalcamera and recorded to a computer. Rats were habituated to the testarena on four occasions prior to testing. Habituation sessionsreplicated the test day sequence exactly with the exception of objectpresentation. On test days, each rat was placed into the test arena and3 minutes later the rat was presented with two identical objects(plastic shapes). The time spent actively exploring the objects during a3-minute test period (T1) was recorded. Following T1 rats were returnedto home cages. After 24 hours each rat was again placed in the testarena and 3 minutes later was presented with one of the now familiarobjects and a novel object, and again the time spent actively exploringthe objects during a 3-minute test period (T2) was recorded. Thepresentation order and position of objects (left/right) was randomisedwithin groups to prevent bias from order or place preference. Objectswere cleaned with 70% ethanol solution between trials to remove anyolfactory/taste cues. Compounds were administered by oral gavage at anappropriate pre-treatment time prior to T1 and T2 (n=12) at dosageranges between 0.03 and 3 mg/kg. In some experiments the 5-HT6 receptorantagonistN-(3,5-dichloro-2-methoxyphenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide(CAS 402713-80-8) (10 mg/kg p.o.; 4 h pre-treatment time) was includedas a positive control. Vehicle controls (1% methylcellulose in water)were included for comparison in each study. Results are expressed as thed2 index (difference in time spent exploring novel and familiarobjects/total object exploration in T2).

Results for Compound Examples 5, 6, 8, 10, 11, 12, 13, 34 and 47 aregiven in Table 3, which shows d2 index values (mean±SEM) for each doseadministered.

TABLE 3 Vehicle Dose 1 Dose 2 Dose 3 CAS 402713-80-8 (1% MCW p.o.)(mg/kg p.o.) (mg/kg p.o.) (mg/kg p.o.) (10 mg/kg p.o.) Ex. [mean ± SEM][mean ± SEM] [mean ± SEM] [mean ± SEM] [mean ± SEM]  5 — 0.03 0.1 0.3 nt[0.00 ± 0.03] [0.04 ± 0.06]  [0.20 ± 0.05]** [0.28 ± 0.05]***  6 — 0.3 13 nt [0.04 ± 0.04] [0.11 ± 0.09]  [0.27 ± 0.08]* [0.36 ± 0.09]**   8 —0.03 0.1 0.3 [0.34 ± 0.05]*** [0.05 ± 0.04] [0.00 ± 0.07] [0.09 ± 0.06][0.34 ± 0.06]*** 10 — 0.03 0.1 0.3 nt [−0.03 ± 0.04]   [0.18 ± 0.10][0.18 ± 0.09] [0.30 ± 0.08]**  11 — 0.3 1 3 — [0.08 ± 0.05] [0.24 ±0.06] [0.24 ± 0.07] [0.31 ± 0.06]**  [0.34 ± 0.04]**  12 — 0.3 1 3 —[0.04 ± 0.05] [0.13 ± 0.06]   [0.30 ± 0.05]*** [0.33 ± 0.06]*** [0.28 ±0.07]*** 13 — 0.3 1 3 — [0.07 ± 0.04] [0.09 ± 0.05] [0.13 ± 0.07] [0.25± 0.09]*  [0.34 ± 0.05]**  34 — 0.1 0.3 1 — [0.04 ± 0.05] [0.08 ± 0.08] [0.24 ± 0.05]* [0.23 ± 0.06]*  [0.27 ± 0.08]*  47 — 0.1 0.3 1 — [−0.02± 0.04]   [0.11 ± 0.09] [0.10 ± 0.05] [0.32 ± 0.07]*** [0.33 ± 0.08]***SEM = standard error of the mean; MCW = methylcellulose in water; p.o. =per os; nt = not tested; *P < 0.05, **P < 0.01, ***P < 0.001 compared tovehicle (ANOVA followed by LSD post-hoc planned comparisons).Novel Object Recognition Test in Scopolamine-Induced Cognitive DeficitCondition

For 2 days before starting the test, 6-week old male Long-Evans ratswere acclimated to experimental operations such as administration and atest device (that is, a black or gray plastic cage with a width of 40cm, a depth of 30 cm and a height of 45 cm). Each test compound wasdissolved in a 0.5% methylcellulose in water to be orally administeredat dosage ranges between 0.01 and 0.1 mg/kg. Thirty minutes after thetest compound administration, scopolamine hydrobromide dissolved in asaline was intraperitoneally administered at a 0.7 mg/kg dose, so as toinduce cognitive impairment. After another 30 minutes, each rat wasacclimated in the test device for 3 minutes, and thereafter, two blocksin the same shape were put in the test device as acquisition trial, andexploring time for each block was measured for 5 minutes. Two hoursafter the acquisition trial, the rat was acclimated in the test devicefor 3 minutes, and thereafter, the same block as those used in theacquisition trial and a new block in a different shape were put in thecage for retention trial. The exploring time for each block was measuredfor 3 minutes, and a ratio of the exploring time for the newly usedblock to the sum of the exploring times for the respective blocks wascalculated as a discrimination index (novel object explorationtime/total object exploration time in retention trial×100). The thusobtained discrimination indexes were compared among a group of rats towhich a vehicle alone was administered (vehicle group), a group of ratsto which scopolamine alone was administered (scopolamine alone group)and a group of rats to which both the test compound and scopolamine wereadministered, so as to evaluate the action of the test compound on thenovel object recognition function (cognitive function) of the rats.

Each discrimination index was shown as an average and a standard error.The statistical significance between the vehicle group and thescopolamine alone group was analyzed by the independent t-test. Thestatistical significance between the scopolamine alone group and eachsample group was analyzed by one-way analysis of variance and then byDunnett's multiple comparison test. The significance level was set to 5%on both sides. If the discrimination index was significantly lower inthe scopolamine alone group than in the vehicle group, it was determinedthat the cognitive impairment was sufficiently induced, and hence, thetest compound was evaluated in the corresponding group. The analysis wascarried out by using Prism 6 for Windows, ver. 6.02. Results forCompound Example 5 are given in Table 4, which shows the discriminationindex for each dose administered.

TABLE 4 Group Scopolamine/ Scopolamine/ Saline/ Scopolamine/ 0.01 mg/kg0.03 mg/kg Scopolamine/ Vehicle Vehicle p.o. p.o. 0.1 mg/kg p.o. N 10 911 11 10 [mean ± SEM] [74.4 ± 2.1] [52.2 ± 4.3] *** [50.5 ± 4.3] [61.7 ±2.5] [72.9 ± 2.6]### SEM = standard error of the mean; p.o. = per os;*** P < 0.001 compared to vehicle group (unpaired t test). ###P < 0.001compared to scopolamine alone group (one-way analysis of variancefollowed by Dunnett multiple comparison test).Morris Water Maze Test in Ibotenic Acid-Induced Learning DisabilityModel

Ibotenic acid at 5 μg/0.5 μL was injected into both basal nuclei of8-week old male Crlj: WI rats, and a Morris water maze test wasperformed 10-14 days after ibotenic acid injection. It has been reportedthat rats in which basal forebrain was lesioned by ibotenic acidinjection show learning disability in the Morris water maze test.(Pharmacopsychiat, 1999, 32, 242-247). The test is considered a model ofspatial learning and memory. Therefore, it is considered to becomparable to spatial learning and memory tests used in human clinicaltesting.

Learning trials were performed twice a day at an interval of 3 hours for4 days (8 times in total), and probe trials were performed once the dayafter completion of the learning trials. Each test compound wasdissolved in a 0.5% methylcellulose in water and orally administered 1hour before the first trial on each day of the learning trials and 1hour before the trial on the day of the probe trials.

A colorless clear acrylic platform (diameter: about 12 cm, height: about30 cm) and a gray vinyl chloride circular pool (diameter: about 148 cm,height: about 44 cm), which was filled with water (temperature: 17-18°C.) up to a height of about 32 cm so that the platform was fullyimmersed in water, were used as the test device. Four quadrants wereprepared at the bottom of the pool, and the platform was set at thecenter of 1 of the 4 quadrants (about 37 cm from the center of thepool). A light bulb was placed near the quadrant with the platform as aspatial cue.

In learning trials, the animal was put into water and goal latency andswimming distance to reach the platform were measured (measurement time:90 seconds at the longest) by a video image behavioral analysis device(Etho Vision XT, Noldus Information Technology Inc.). When an animalreached the platform within 90 seconds and stayed on the platform for 30seconds, it was judged that the animal recognized the position of theplatform, and the measurement was finished. When an animal failed toreach the platform within 90 seconds, the goal latency for that animalwas recorded as 90 seconds. Any animal which failed to reach theplatform within 90 seconds was placed on the platform for 30 secondsafter the measurement and returned to the cage. When an animal reachedthe platform and went into the water again, it was judged that theanimal failed to recognize the position of the platform, and themeasurement was continued.

In probe trials, the platform was removed from the pool. The animal wasput into water, and the swimming time in the quadrant where the platformhad been located in the learning trials and the frequency of entry intothe platform area where the platform had been located in the learningtrials were measured by Etho Vision XT.

Each value was shown as an average and a standard error (n=10). Thestatistical significance between a control group and a vehicle group wasanalyzed by the independent t-test. The statistical significance betweenthe vehicle group and each sample group was analyzed by one-way analysisof variance and then by Dunnett's multiple comparison test. Thesignificance level was set to 5% on both sides. If the values weresignificantly higher or lower in the vehicle group than in the controlgroup, it was determined that the cognitive impairment was sufficientlyinduced, and hence, the test compound was evaluated in the correspondinggroup. The analysis was carried out by using SAS system (SAS InstituteJapan Ltd.). Results for Compound Example 5 are given in Table 5.

TABLE 5 Control¹ Vehicle² 0.1 mg/kg p.o.³ 0.3 mg/kg p.o.³ Group [mean ±SEM] [mean ± SEM] [mean ± SEM] [mean ± SEM] Goal Trial 1 [82.63 ± 4.51]   [90 ± 0.00]   [90 ± 0.00]   [90 ± 0.00] latency Trial 2 [72.85 ±8.29]    [90 ± 0.00]   [90 ± 0.00] [89.47 ± 0.53]  (sec.) Trial 3 [56.39± 10.63]    [90 ± 0.00]** [78.81 ± 8.1]  [75.08 ± 7.99]  Trial 4 [59.98± 10.14]    [90 ± 0.00]** [79.59 ± 7.36]  [60.53 ± 12.15]# Trial 5[31.47 ± 10.1]     [90 ± 0.00]** [83.06 ± 4.7]  [53.99 ± 10.18]## Trial6 [22.7 ± 6.25]    [90 ± 0.00]** [66.13 ± 12.22] [33.09 ± 9.78]##  Trial7 [19.89 ± 6.73]     [90 ± 0.00]** [76.97 ± 8.11]   [50.1 ± 10.02]##Trial 8 [13.38 ± 4.13]     [90 ± 0.00]** [67.24 ± 10.13] [38.02 ±10.74]## Swimming Trial 1 [2294.57 ± 175.61]  [2164.75 ± 92.56] [2152.96 ± 91.73]  [2400.75 ± 122.49]  distance Trial 2 [2254.05 ±236.92]  [2163.93 ± 170.94]  [2353.99 ± 145.71]  [2533.19 ± 86.87]  (cm)Trial 3 [1815.75 ± 297.48]  [2421.72 ± 155.56]  [1884.79 ± 174.8] [1945.42 ± 189.94]  Trial 4 [1551.88 ± 243.76]  [2129.56 ± 238.64] [1822.32 ± 206.29]  [1592.82 ± 308.21]  Trial 5 [961.27 ± 258.64] [2333.29 ± 189.64]** [1918.78 ± 132.12]  [1417.94 ± 229.44]##  Trial 6[663.17 ± 160.79]  [2148.48 ± 153.69]** [1464.97 ± 308.91]   [876.2 ±203.14]## Trial 7 [603.49 ± 134.79] [2290.57 ± 207.2]** [1839.16 ±221.78]  [1329.27 ± 236.21]##  Trial 8 [428.85 ± 107.74]  [2053.14 ±190.71]** [1492.52 ± 260.05]  [1020.57 ± 253.94]##  Swimming 0-30 sec.[8.84 ± 1.53]  [5.21 ± 0.76]* [8.90 ± 1.02]# [7.19 ± 1.11] time 30-60[9.54 ± 1.27]  [4.67 ± 1.02]** [9.41 ± 1.80]# [8.48 ± 1.25] in 4^(th)sec. quadrant 60-90 [9.41 ± 1.33]  [5.60 ± 0.76]* [7.74 ± 0.85] [7.49 ±1.37] (sec.) sec. Total [27.79 ± 3.42]   [15.48 ± 2.15]** [26.05 ±2.03]## [23.16 ± 2.97]  Frequency of entry [4.2 ± 0.6]  [0.0 ± 0.0]**[0.9 ± 0.3] [1.7 ± 0.5]## into platform area SEM = standard error of themean; p.o. = per os; *P < 0.05, **P < 0.01 compared to control group(unpaired t test). #P < 0.05, ##P < 0.01 compared to vehicle group(one-way analysis of variance followed by Dunnett multiple comparisontest). ¹Control group animals were placed under anaesthetic (withoutibotenic acid injection) and then administered vehicle prior to testing²Vehicle group animals received an ibotenic acid injection underanaesthetic and then administered vehicle prior to testing ³Sample groupanimals received an ibotenic acid injection under anaesthetic and thenadministered test compound prior to testing

The invention claimed is:
 1. A compound, or a pharmaceuticallyacceptable salt thereof, which is1-(4-fluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.2. A compound, or a pharmaceutically acceptable salt thereof, which is1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.3. A compound, or a pharmaceutically acceptable salt thereof, which is1-(2,3-difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.4. A method for positive allosteric modulation of muscarinic receptormAChR M1, comprising administering to a human subject in need thereof aneffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.
 5. A method for symptomatictreatment of cognitive impairment in Alzheimer-type dementia (AD),comprising administering to a human subject in need thereof atherapeutically effective amount of the compound according to claim 1,or a pharmaceutically acceptable salt thereof.
 6. A method forsymptomatic treatment of cognitive impairment in dementia with Lewybodies (DLB), comprising administering to a human subject in needthereof a therapeutically effective amount of the compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition comprising the compound according to claim 1,or a pharmaceutically acceptable salt thereof, as an active ingredientin association with a pharmaceutically acceptable carrier.
 8. A methodfor positive allosteric modulation of muscarinic receptor mAChR M1,comprising administering to a human subject in need thereof an effectiveamount of the compound according to claim 2, or a pharmaceuticallyacceptable salt thereof.
 9. A method for symptomatic treatment ofcognitive impairment in Alzheimer-type dementia (AD), comprisingadministering to a human subject in need thereof a therapeuticallyeffective amount of the compound according to claim 2, or apharmaceutically acceptable salt thereof.
 10. A method for symptomatictreatment of cognitive impairment in dementia with Lewy bodies (DLB),comprising administering to a human subject in need thereof atherapeutically effective amount of the compound according to claim 2,or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising the compound according to claim 2, or apharmaceutically acceptable salt thereof, as an active ingredient inassociation with a pharmaceutically acceptable carrier.
 12. A method forpositive allosteric modulation of muscarinic receptor mAChR M1,comprising administering to a human subject in need thereof an effectiveamount of the compound according to claim 3, or a pharmaceuticallyacceptable salt thereof.
 13. A method for symptomatic treatment ofcognitive impairment in Alzheimer-type dementia (AD), comprisingadministering to a human subject in need thereof a therapeuticallyeffective amount of the compound according to claim 3, or apharmaceutically acceptable salt thereof.
 14. A method for symptomatictreatment of cognitive impairment in dementia with Lewy bodies (DLB),comprising administering to a human subject in need thereof atherapeutically effective amount of the compound according to claim 3,or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising the compound according to claim 3, or apharmaceutically acceptable salt thereof, as an active ingredient inassociation with a pharmaceutically acceptable carrier.